(R)-8-(1-((3-fluorophenyl)amino)ethyl)-N-(2-hydroxyethyl)-2-morpholinoquinoxaline-6-carboxamide for inhibiting phosphoinositide-3-kinase activity

ABSTRACT

The present invention relates to substituted quinoxaline and pyridopyrazine derivatives of Formula (I) 
                         
wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as pI3Kβ inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application claiming priority ofnational stage application of International Patent Application No.PCT/EP2016/073962, filed 7 Oct. 2016, which claims priority from EPApplication 15189163.7 filed 9 Oct. 2015 and EP Application 16174710.0filed on 16 Jun. 2016. The complete disclosures of the aforementionedrelated patent applications are hereby incorporated herein by referencefor all purposes.

FIELD OF THE INVENTION

The present invention relates to substituted quinoxaline andpyridopyrazine derivatives useful as PI3Kβ inhibitors. The inventionfurther relates to pharmaceutical compositions comprising said compoundsas an active ingredient as well as the use of said compounds as amedicament.

BACKGROUND OF THE INVENTION

There are three classes of phosphoinositide-3-kinases (PI3Ks): class I,class II and class III. Class I PI3Ks are the most associated with humancancer [K. D Courtney, R. B. Corcoran and J. A. Engelman (2010), Journalof Clinical Oncology., 28; 1075]. The class I phosphoinositide-3-kinases(PI3Ks) are divided into 2 subclasses: class I_(A), composed of a p110catalytic subunit (p110a, p110b or p110d) and a p85 regulatory subunit(p85a, p55a and p50a, p85b or p55g) and class I_(B) PI3K represented bythe p110g catalytic subunit and the p101 and p84 regulatory subunits [B.Vanhaesebroeck and M. D. Waterfield (1999) Experimental Cell Research.,253, 239-254]. The class I_(A) PI3Ks are activated in a variety of solidand non-solid tumors via mutation or deletion of the tumor suppressorPTEN (phosphatase and tensin homolog) or in the case of p110a byactivating mutations [K. D Courtney, R. B. Corcoran and J. A. Engelman(2010), Journal of Clinical Oncology., 28; 1075]. PI3Ks can also beactivated by receptor tyrosine kinases (RTKs); p110b can be activated byG-protein coupled receptors [K. D Courtney, R. B. Corcoran and J. A.Engelman (2010), Journal of Clinical Oncology., 28; 10751. Onceactivated the phosphoinositide-3-kinases catalyze the phosphorylation ofphosphatidyl 4,5-diphosphate leading to the generation of phosphatidyl,3, 4, 5-triphosphate (PIP3) [Zhao L., Vogt P. K. (2008) Oncogene 27,5486-54961. PTEN antagonizes the activity of the PI3Ks through thedephosphorylation PIP3 [Myers M. P., Pass I., Batty I. H., Van der KaayJ., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N.K. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 13513-135181. The PIP3generated by activation of PI3K or sustained by the inactivation of PTENbinds to a subset of lipid-binding domains in downstream targets such asthe pleckstrin homology domain of the oncogene Akt thereby recruiting itto the plasma membrane [Stokoe D., Stephens L. R., Copeland T., GaffneyP. R., Reese C. B., Painter G. F., Holmes A. B., McCormick F., HawkinsP. T. (1997) Science 277, 567-5701. Once at the plasma membrane Aktphosphorylates several effector molecules that are involved in numerousbiologically relevant processes such as metabolism, differentiation,proliferation, longevity and apoptosis [D. R. Calnan and A. Brunet(2008) Oncogene 27; 2276)].

Several studies suggest a key role for p110b in PTEN-deficient tumors.For example the genetic knockout of p110b, but not p110a, is able toblock tumor formation and Akt activation driven by Pten loss in theanterior prostate in a mouse model [Jia S, Liu Z, Zhang S, Liu P, ZhangL, Lee S H, Zhang J, Signoretti S, Loda M, Roberts T M, Zhao J J. Nature2008; 454:776-91. Furthermore other studies have shown that a subset ofPTEN-deficient human tumor cell lines is sensitive to inactivation ofp110b rather than p110a [Wee S, Wiederschain D, Maira S M, Loo A, MillerC, deBeaumont R, Stegmeier F, Yao Y M, Lengauer C (2008) Proc. Nal.Acad. Sci (USA); 105 130571. PTEN deficiency either by geneticinactivation or reduced expression frequently occurs in human cancerssuch as GBM, endometrial, lung, breast cancers and prostate cancer amongothers [K. D Courtney, R. B. Corcoran and J. A. Engelman (2010), Journalof Clinical Oncology., 28; 10751.

These studies suggest that treatment of PTEN-deficient cancer withagents that inhibition p110b may be therapeutically beneficial. Inaddition to its role in cancer, p110b may be a target for antithrombotictherapy. It has been reported in mouse models that PI3Kb inhibition canprevent stable integrin a_(IIb)b₃ adhesion contacts that eliminatesocculusive thrombus formation without prolongation of bleed time [S. P.Jackson et al. (2005) Nature Medicine., 11, 507-5141.

Furthermore, the phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/AKT pathway is frequently activated during prostate cancer (PCa)progression through loss or mutation of the phosphatase and tensinhomolog (PTEN) gene. Following the androgen receptor (AR) pathway, it isthe second major driver of PCa growth. Combination with hormonal therapyimproved efficacy of PI3K/AKT-targeted agents in PTEN-negative PCamodels. Upregulation of AR-target genes upon PI3K/AKT inhibitionsuggests a compensatory crosstalk between the PI3K-AR pathways which,for optimal efficacy treatment, could require cotargeting of the AR axis[Marques R B, et al., High Efficacy of Combination Therapy UsingPI3K/AKT Inhibitors with Androgen Deprivation in Prostate CancerPreclinical Models. Eur Urol (2014),http://dx.doi.org/10.1016/j.eururo.2014.08.053]. Therefore PI3Kβinhibitors can be advantageously combined with anti-androgen therapiesincluding androgen receptor antagonists and inhibitors of androgenbiosynthesis in PTEN-negative prostate cancers.

WO 2012/116237 discloses heterocyclic entitites that modulate PI3 kinaseactivity.

WO 2011/123751 describes heterocyclic compounds as selective inhibitorsof PI3K activity.

WO 2011/022439 discloses heterocyclic entities that modulate PI3 kinaseactivity.

WO 2008/014219 describes thiozolidinedione derivatives as PI3 kinaseinhibitors.

WO 2013/028263 relates to pyrazolopyrimidine derivatives as PI3 kinaseinhibitors.

WO 2012/047538 relates to benzimidazole derivatives as PI3 kinaseinhibitors.

WO 2013/095761 relates to imidazopyridine derivatives as PI3 kinaseinhibitors.

US 2013/0157977 relates to benzimidazole boronic acid derivatives as PI3kinase inhibitors.

WO 2009/021083 describes quinoxaline derivatives as PI3 kinaseinhibitors.

WO 2007/103756 describes the preparation of thiazolones for use as PI3kinase inhibitors.

WO 2011/041399 describes benzimidazolyl (morpholinyl) purines andrelated compounds as PI3K8 inhibitors and their preparation and use forthe treatment of PI3K-mediated diseases.

WO 2009/088990 describes the preparation of pyrazolo pyrimidines andother heterocyclic compounds as therapeutic PI3 kinase modulators.

WO2016/097347 relates to substituted imidazopyridazine derivativesuseful as PI3Kβ inhibitors.

WO2016/097359 relates to relates to heterocyclyl linkedimidazopyridazine derivatives useful as PI3Kβ inhibitors.

There is thus a strong need for novel PI3Kβ kinase inhibitors therebyopening new avenues for the treatment or prevention of cancer, inparticular PTEN-deficient cancers, more in particular prostate cancer.It is accordingly an object of the present invention to provide suchcompounds.

SUMMARY OF THE INVENTION

It has been found that the compounds of the present invention are usefulas PI3Kβ inhibitors. The compounds according to the invention andcompositions thereof, may be useful for the treatment or prevention, inparticular for the treatment, of diseases such as cancer, autoimmunedisorders, cardiovascular diseases, inflammatory diseases,neurodegenerative diseases, allergy, pancreatitis, asthma, multiorganfailure, kidney diseases, platelet aggregation, sperm motility,transplantation rejection, graft rejection, lung injuries and the like.

This invention concerns compounds of Formula (I)

tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b).

R^(1a) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one—OH;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(6b), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂— or —(CH₂)₄—;

R² represents

R^(6a) and R^(6b) each independently are selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(6c) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², —C(═O)—NH—C₁₋₄alkyl-Het¹,—C(═O)—N(C₁₋₄alkyl)-C₁₋₄alkyl-Het¹, —C(═O)—N(C₁₋₄alkyl)-Het², C₁₋₄alkyl,—CH═N—OH, —CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂-Het¹,—CH(OH)—C₁₋₄alkyl, —C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkylsubstituted with one substituent selected from the group consisting ofhydroxyl, fluoro, —NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —(C═O)—O—C₁₋₄alkyl, —(C═O)—OH,—(C═O))—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and C₁₋₄alkyl substituted with one substituent selectedfrom the group consisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—NH₂, —NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N; or Het¹ represents abicyclic 8-, 9- or 10-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo,—NR^(9a)R^(9b), C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms; Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

Ar represents phenyl optionally substituted with one hydroxyl;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

The present invention also concerns methods for the preparation ofcompounds of the present invention and pharmaceutical compositionscomprising them.

The compounds of the present invention were found to inhibit PI3Kβ perse or can undergo metabolism to a (more) active form in vivo (prodrugs),and therefore may be useful in the treatment or prevention, inparticular in the treatment, of diseases such as cancer, autoimmunedisorders, cardiovascular diseases, inflammatory diseases,neurodegenerative diseases, allergy, pancreatitis, asthma, multiorganfailure, kidney diseases, platelet aggregation, sperm motility,transplantation rejection, graft rejection, lung injuries and the like.

In view of the aforementioned pharmacology of the compounds of Formula(I) and N-oxides, pharmaceutically acceptable addition salts, andsolvates thereof, it follows that they may be suitable for use as amedicament.

In particular the compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, may besuitable in the treatment or prevention, in particular in the treatment,of cancer.

The present invention also concerns the use of compounds of Formula (I)and N-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament for the inhibition ofPI3Kβ, for the treatment or prevention of cancer. The present inventionwill now be further described. In the following passages, differentaspects of the invention are defined in more detail. Each aspect sodefined may be combined with any other aspect or aspects unless clearlyindicated to the contrary. In particular, any feature indicated as beingpreferred or advantageous may be combined with any other feature orfeatures indicated as being preferred or advantageous.

DETAILED DESCRIPTION OF THE INVENTION

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise.

When any variable occurs more than one time in any constituent or in anyformula (e.g. Formula (I)), its definition in each occurrence isindependent of its definition at every other occurrence.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, in particular from 1 to 3hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

When two or more substituents are present on a moiety they may, unlessotherwise is indicated or is clear from the context, replace hydrogenson the same atom or they may replace hydrogen atoms on different atomsin the moiety.

It will be clear for the skilled person that, unless otherwise isindicated or is clear from the context, a substituent on a heterocyclylgroup may replace any hydrogen atom on a ring carbon atom or on a ringheteroatom.

The prefix “C_(x-y)” (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl groupcontains from 1 to 6 carbon atoms, a C₁₋₄alkyl group contains from 1 to4 carbon atoms, a C₁₋₃alkyl group contains from 1 to 3 carbon atoms, aC₃₋₆cycloalkyl group contains from 3 to 6 carbon atoms, and so on.

The term “halo” as a group or part of a group is generic for fluoro,chloro, bromo, iodo unless otherwise is indicated or is clear from thecontext.

The term “C₁₋₆alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numberranging from 1 to 6. C₁₋₆alkyl groups comprise from 1 to 6 carbon atoms,preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbonatoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may belinear or branched and may be substituted as indicated herein. When asubscript is used herein following a carbon atom, the subscript refersto the number of carbon atoms that the named group may contain. Thus,for example, C₁₋₆alkyl includes all linear, or branched alkyl groupswith between 1 and 6 carbon atoms, and thus includes such as for examplemethyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers(e.g. n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyland its isomers, and the like.

The term “C₁₋₄alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numberranging from 1 to 4. C₁₋₄alkyl groups comprise from 1 to 4 carbon atoms,preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbonatoms. C₁₋₄alkyl groups may be linear or branched and may be substitutedas indicated herein. When a subscript is used herein following a carbonatom, the subscript refers to the number of carbon atoms that the namedgroup may contain. C₁₋₄alkyl includes all linear, or branched alkylgroups with between 1 and 4 carbon atoms, and thus includes methyl,ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers (e.g.n-butyl, isobutyl and tert-butyl), and the like.

The term “C₃₋₆cycloalkyl” alone or in combination, refers to a cyclicsaturated hydrocarbon radical having from 3 to 6 carbon atoms.Non-limiting examples of suitable C₃₋₆cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

Examples of compounds wherein R^(1b) and R^(1a) are taken together toform —(CH₂)₃— are compounds 1-4, 10, 14-19, 23-52, 54-55, 57-58, 62-67,69-72, 75-77, 93-96, 101-103, 106-107, 112, 249-255.

Examples of compounds wherein R^(1b) and R^(1c) are taken together toform —(CH₂)₃— are compounds 244-245.

In case L represents —CH(C₁₋₄alkyl)-CH₂—, it is intended that the C-atomwith the two hydrogens (—CH₂—) is attached to the phenyl ring in thestructure of formula (I).

In case L represents —CH₂—CH(C₁₋₄alkyl)-, it is intended that the C-atomwith the C₁₋₄alkyl substituent (—CH(C₁₋₄alkyl)-) is attached to thephenyl ring in the structure of formula (I).

In case L represents —CHR^(1a)—X—, it is intended that ‘X’ is attachedto the phenyl ring in the structure of formula (I).

In case L represents —X—CHR^(1c)—, it is intended that the C-atom withthe Ric substituent (—CHR^(1c)—) is attached to the phenyl ring in thestructure of formula (I).

In an embodiment the expression ‘at least one heteroatom’ is restrictedto ‘1, 2 or 3 heteroatoms’, in a particular embodiment to ‘1 or 2heteroatoms’, in a more particular embodiment to ‘1 heteroatom’.

Examples of a 4-, 5- or 6-membered saturated heterocyclyl containing atleast one heteroatom each independently selected from O, S, S(═O)_(p)and N (e.g. in Ring A), include, but are not limited to azetidinyl,morpholinyl, piperidinyl, pyrrolidinyl, 1,1-dioxido-thietanyl,1,1-dioxido-thiomorpholinyl, piperazinyl, dioxolanyl, oxazolidinyl,oxetanyl, tetrahydrofuranyl, and the like.

Examples of a 4-, 5-, 6- or 7-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N (e.g. in Het¹), include, but are notlimited to azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl,1,1-dioxido-thietanyl, 1,1-dioxido-thiomorpholinyl, piperazinyl,dioxolanyl, oxazolidinyl, oxetanyl, tetrahydrofuranyl,4,5-dihydro-1,3-oxazolyl, hexahydro-1H-1,4-diazepinyl, and the like.

Examples of a bicyclic 8-, 9- or 10-membered saturated or partiallysaturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N (e.g. in Het¹),include, but are not limited to4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,octahydro-pyrrolo[1,2-a]pyrazinyl, and the like.

Het¹ representing a bicyclic heterocyclyl, in particular is a fusedbicyclic heterocyclyl.

Het¹ may be attached to the remainder of the molecule of Formula (I)through any available ring carbon atom or ring heteroatom asappropriate, if not otherwise specified. In a particular embodiment Het¹is attached to the remainder of the molecule of Formula (I) via anitrogen atom.

It will be clear that when two substituents on the same carbon atom inthe Het¹ definition are taken together to form together with the commoncarbon atom to which they are attached Ring A, a spiro moiety is formed.For example, when Het¹ represents 1-piperidinyl wherein two substituentson the carbon atom in position β are taken together to form togetherwith the common carbon atom to which they are attached ring A, thefollowing spiro moiety is formed:

in particular if in the above example ring A represents 3-azetidinyl,the following spiro moiety is formed:

Examples of such spiro moieties, include, but are not limited to

and the like.

Whenever substituents are represented by chemical structure, “---”represents the bond of attachment to the remainder of the molecule ofFormula (I).

Whenever one of the ring systems, is substituted with one or moresubstituents, those substituents may replace, unless otherwise isindicated or is clear from the context, any hydrogen atom bound to acarbon or nitrogen atom of the ring system.

The term “subject” as used herein, refers to an animal, preferably amammal (e.g. cat, dog, primate or human), more preferably a human, whois or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medicinal doctor orother clinician, which includes alleviation or reversal of the symptomsof the disease or disorder being treated.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “treatment”, as used herein, is intended to refer to allprocesses wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease, but does not necessarilyindicate a total elimination of all symptoms.

The term “compounds of the invention” as used herein, is meant toinclude the compounds of Formula (I) and N-oxides, pharmaceuticallyacceptable addition salts, and solvates thereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the term “compound of Formula (I)” ismeant to include the stereoisomers thereof and the tautomeric formsthereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture.

Atropisomers (or atropoisomers) are stereoisomers which have aparticular spatial configuration, resulting from a restricted rotationabout a single bond, due to large steric hindrance. All atropisomericforms of the compounds of Formula (I) are intended to be included withinthe scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e. they are not related as mirror images. If a compoundcontains a double bond, the substituents may be in the E or the Zconfiguration. Substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration; for example ifa compound contains a disubstituted cycloalkyl group, the substituentsmay be in the cis or trans configuration. Therefore, the inventionincludes enantiomers, atropisomers, diastereomers, racemates, E isomers,Z isomers, cis isomers, trans isomers and mixtures thereof, wheneverchemically possible.

The meaning of all those terms, i.e. enantiomers, atropisomers,diastereomers, racemates, E isomers, Z isomers, cis isomers, transisomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other stereoisomers. Thus, when a compound ofFormula (I) is for instance specified as (R), this means that thecompound is substantially free of the (S) isomer; when a compound ofFormula (I) is for instance specified as E, this means that the compoundis substantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds of Formula (I) may also exist in their tautomericform. Such forms in so far as they may exist, are intended to beincluded within the scope of the present invention. It follows that asingle compound may exist in both stereoisomeric and tautomeric form.For example, it will be clear for the skilled person that when R⁷represent

also

is included.

For therapeutic use, salts of the compounds of Formula (I), N-oxides andsolvates thereof, are those wherein the counterion is pharmaceuticallyacceptable. However, salts of acids and bases which arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveor hereinafter are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds ofFormula (I), N-oxides and solvates thereof, are able to form. Thepharmaceutically acceptable acid addition salts can conveniently beobtained by treating the base form with such appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely said salt formscan be converted by treatment with an appropriate base into the freebase form.

The compounds of Formula (I), N-oxides and solvates thereof containingan acidic proton may also be converted into their non-toxic metal oramine addition salt forms by treatment with appropriate organic andinorganic bases. Appropriate base salt forms comprise, for example, theammonium salts, the alkali and earth alkaline metal salts, e.g. thelithium, sodium, potassium, magnesium, calcium salts and the like, saltswith organic bases, e.g. primary, secondary and tertiary aliphatic andaromatic amines such as methylamine, ethylamine, propylamine,isopropylamine, the four butylamine isomers, dimethylamine,diethylamine, diethanolamine, dipropylamine, diisopropylamine,di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine,triethylamine, tripropylamine, quinuclidine, pyridine, quinoline andisoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts,and salts with amino acids such as, for example, arginine, lysine andthe like. Conversely the salt form can be converted by treatment withacid into the free acid form.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of Formula (I) are able to form, as well as N-oxides andpharmaceutically acceptable addition salts thereof. Examples of suchforms are e.g. hydrates, alcoholates and the like.

The compounds of the invention as prepared in the processes describedbelow may be synthesized in the form of mixtures of enantiomers, inparticular racemic mixtures of enantiomers, that can be separated fromone another following art-known resolution procedures. A manner ofseparating the enantiomeric forms of the compounds of Formula (I), andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, involves liquid chromatography using a chiral stationary phase.Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

In the framework of this application, an element, in particular whenmentioned in relation to a compound of Formula (I), comprises allisotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ²H, ³H,¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably,the radioactive isotope is selected from the group of ²H, ³H, ¹¹C and¹⁸F. More preferably, the radioactive isotope is ²H. In particular,deuterated compounds are intended to be included within the scope of thepresent invention.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one—OH;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(6b), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with Ria or Ric to form —(CH₂)₃—;

or R^(1b) is taken together with Ric to form —(CH₂)₂— or —(CH₂)₄—;

R² represents

R^(6a) and R^(6b) each independently are selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(6c) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂-Het¹, —CH(OH)—C₁₋₄alkyl,—C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, fluoro,—NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —(C═O)—O—C₁₋₄alkyl, —(C═O)—OH,—(C═O)—C₁₋₄alkyl, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h).

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N; or Het¹ represents abicyclic 8-, 9- or 10-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo,—NR^(9a)R^(9b), C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

Ar represents phenyl optionally substituted with one hydroxyl;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(6b), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂- or —(CH₂)₄—;

R² represents

R^(6a) and R^(6b) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(6c) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂-Het¹, —CH(OH)—C₁₋₄alkyl,—C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, fluoro,—NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(bf),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N; or Het¹ represents abicyclic 8-, 9- or 10-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

Ar represents phenyl optionally substituted with one hydroxyl;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl,—O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂— or —(CH₂)₄—;

R² represents

R^(6C) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂-Het¹, —CH(OH)—C₁₋₄alkyl,—C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, fluoro,—NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N; or Het¹ represents abicyclic 8-, 9- or 10-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆ alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one—OH;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl,—O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂— or —(CH₂)₄—;

R² represents

R^(6c) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², —C(═O)—NH—C₁₋₄alkyl-Het¹,—C(═O)—N(C₁₋₄alkyl)-C₁₋₄alkyl-Het¹, —C(═O)—N(C₁₋₄alkyl)-Het², C₁₋₄alkyl,—CH═N—OH, —CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹,—CH(OH)—C₁₋₄alkyl, —C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkylsubstituted with one substituent selected from the group consisting ofhydroxyl, fluoro, —NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —(C═O)—O—C₁₋₄alkyl, —(C═O)—OH, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂; R^(4a), R^(4b) and R^(4c) eachindependently are selected from the group consisting of hydrogen, cyano,C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f), —O—C₁₋₄alkyl, and C₁₋₄alkylsubstituted with one or more substituents each independently selectedfrom the group consisting of hydroxyl, halo, and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N; or Het¹ represents abicyclic 8-, 9- or 10-membered saturated or partially saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl.—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one—OH;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂—;

R² represents

R³ represents R⁷, —(C═O)H, —(C═O)—NR^(5a)R^(5b), —(C═O)—OR^(5c),—C(═O)-Het¹, —C(═O)—NH—Het², —C(═O)—NH—C₁₋₄alkyl-Het¹,—C(═O)—N(C₁₋₄alkyl)-Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹, —CH(OH)—C₁₋₄alkyl, halo, orR³ represents C₁₋₄alkyl substituted with one substituent selected fromthe group consisting of hydroxyl, fluoro, —NR^(5f)R^(5g), Het¹, and—O—C₁₋₄alkyl-OH;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —O—C₁₋₄alkyl-NH₂,—O—C₁₋₄alkyl-NH(C₁₋₄alkyl), —(C═O)—O—C₁₋₄alkyl, —(C═O)—OH,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —S(═O)₂—C₁₋₄alkyl;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onehydroxyl substituent;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S(═O)_(p) and N;

or Het¹ represents a bicyclic 9-membered saturated or partiallysaturated heterocyclyl containing at least one N-atom;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), hydroxyl, —O—C₁₋₄alkyl, C₁₋₄alkyl substitutedwith one or more halo atoms, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl and—NH(C₁₋₄alkyl); or two substituents on the same carbon atom of saidheterocyclyl are taken together to form together with the common carbonatom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1;

n2 represents 1 or 2;

R⁸ represents hydrogen, or C₁₋₄alkyl substituted with one or more haloatoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents a 4-membered saturated heterocyclyl containing atleast one heteroatom each independently selected from O, and S(═O)_(p);

p represents 2;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

R² represents

R³ represents R⁷, —(C═O)H, —(C═O)—NR^(5a)R^(5b), —(C═O)—OR^(5c),—C(═O)—Het¹, —C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹, —CH(OH)—C₁₋₄alkyl, halo, orR³ represents C₁₋₄alkyl substituted with one substituent selected fromthe group consisting of hydroxyl, —NR^(5f)R^(5g), Het¹, and—O—C₁₋₄alkyl-OH;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —O—C₁₋₄alkyl-NH₂,—O—C₁₋₄alkyl-NH(C₁₋₄alkyl), —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —S(═O)₂—C₁₋₄alkyl;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, and C₁₋₄alkyl substituted with one —NH₂substituent;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onehydroxyl substituent;

Het¹ represents a monocyclic 4-, 5-, or 6-membered saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S(═O)_(p) and N; or Het¹ represents a bicyclic9-membered partially saturated heterocyclyl containing at least oneN-atom;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of —NR^(9a)R^(9b),C₁₋₄alkyl, —(C═O)—OR^(5h), hydroxyl, —O—C₁₋₄alkyl, C₁₋₄alkyl substitutedwith one or more halo atoms, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, and—NH(C₁₋₄alkyl); or two substituents on the same carbon atom of saidheterocyclyl are taken together to form together with the common carbonatom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, and C₁₋₄alkyl substituted with one or more haloatoms;

Het² represents

n1 represents 1;

n2 represents 1;

R⁸ represents C₁₋₄alkyl substituted with one or more halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents a 4-membered saturated heterocyclyl containing atleast one heteroatom each independently selected from O and S(═O)_(p);

p represents 2;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

Another embodiment of the present invention relates to those compoundsof Formula (I) and the N-oxides, the pharmaceutically acceptableaddition salts, and the solvates thereof, or any subgroup thereof asmentioned in any of the other embodiments wherein one or more of thefollowing restrictions apply:

(i) L represents —CHR^(1a)—X—, or —X—CHR^(1c)—;

(ii) R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

(iii) R² represents

(iv) R³ represents R⁷, —(C═O)H, —(C═O)—NR^(5a)R^(5b), —(C═O)—OR^(5c),—C(═O)-Het¹, —C(═O)—NH-Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹, —CH(OH)—C₁₋₄alkyl, halo, orR³ represents C₁₋₄alkyl substituted with one substituent selected fromthe group consisting of hydroxyl, —NR^(5f)R^(5g), Het¹, and—O—C₁₋₄alkyl-OH;

(v) R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —O—C₁₋₄alkyl-NH₂,—O—C₁₋₄alkyl-NH(C₁₋₄alkyl), —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

(vi) R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and C₁₋₄alkyl substituted with one substituent selectedfrom the group consisting of hydroxyl, —O—C₁₋₄alkyl, and—S(═O)₂—C₁₋₄alkyl;

(vii) R^(6e) and R^(6F) each independently are selected from the groupconsisting of hydrogen, and C₁₋₄alkyl substituted with one —NH₂substituent;

(viii) R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onehydroxyl substituent;

(ix) Het¹ represents a monocyclic 4-, 5-, or 6-membered saturatedheterocyclyl containing at least one heteroatom each independentlyselected from O, S(═O)_(p) and N;

or Het¹ represents a bicyclic 9-membered partially saturatedheterocyclyl containing at least one N-atom;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of —NR^(9a)R^(9b),C₁₋₄alkyl, —(C═O)—OR^(5h), hydroxyl, —O—C₁₋₄alkyl, C₁₋₄alkyd substitutedwith one or more halo atoms, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, and —NH(C₁₋₄alkyl); or two substituents on the same carbon atom of said heterocyclylare taken together to form together with the common carbon atom to whichthey are attached Ring A;

(x) R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, and C₁₋₄alkyl substituted with one or more haloatoms;

(xi) n1 represents 1;

n2 represents 1;

(xii) R⁸ represents C₁₋₄ alkyl substituted with one or more halo atoms;

(xiii) Ring A represents a 4-membered saturated heterocyclyl containingat least one heteroatom each independently selected from O andS(═O)_(p);

(xiv) p represents 2;

(xv) R⁷ represents

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³ or N;

L represents —CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-,—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-, —CHR^(1a)—X—, or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(bb), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

R² represents

R^(6a) and R^(6b) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(6c) and R^(6d) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R³ represents R⁷, —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH,—CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹, —CH(OH)—C₁₋₄alkyl,—C(OH)(C₁₋₄alkyl)₂, halo, or R³ represents C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, fluoro,—NR^(5f)R^(5g), Het¹, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5d) and R^(5e) each independently are selected from the groupconsisting of hydrogen and C₁₋₄ alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl, —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl.—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two

substituents on the same carbon atom of said heterocyclyl are takentogether to form together with the common carbon atom to which they areattached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms; Ring A represents cyclobutyl, cyclopentyl, cyclohexyl,or a 4-, 5- or 6-membered saturated heterocyclyl containing at least oneheteroatom each independently selected from O, S, S(═O)_(p) and N; saidcyclobutyl, cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturatedheterocyclyl is optionally substituted with one or two C₁₋₄alkylsubstituents, with one C₁₋₄alkyl and one hydroxy substituent, or withone hydroxy substituent;

p represents 1 or 2;

Ar represents phenyl optionally substituted with one hydroxyl;

R⁷ represents

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³;

L represents —CHR^(1a)—X— or —X—CHR^(1c)—;

X represents O, S, or NR^(1b);

R^(1a) represents hydrogen or C₁₋₄alkyl; in particular C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₃—;

R² represents

R³ represents —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het² or R³ represents C₁₋₄alkylsubstituted with one —NR^(5f)R^(5g) substituent;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl, C₁₋₄alkyl substituted withone or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onehydroxyl substituent;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, ˜C(═O)H, —NR^(6e)R^(6f),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆ alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two

substituents on the same carbon atom of said heterocyclyl are takentogether to form together with the common carbon atom to which they areattached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³;

L represents —CHR^(1a)—X— or —X—CHR^(1c)—;

X represents NR^(1b);

R^(1a) represents hydrogen or C₁₋₄alkyl; in particular C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₃—;

R² represents

R³ represents —(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹, or R³ representsC₁₋₄alkyl substituted with one —NR^(5f)R^(5g) substituent;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5f) and R^(5g) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onehydroxyl substituent;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, and halo;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of C₁₋₄alkyl;

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³;

L represents —CHR^(1a)—X—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

R² represents

R³ represents —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b),—(C═O)—OR^(5c), —C(═O)-Het¹, —C(═O)—NH—Het²;

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(5c) represents hydrogen or C₁₋₄alkyl;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, —C(═O)H, —NR^(6e)R^(6i),—O—C₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more substituentseach independently selected from the group consisting of hydroxyl, halo,and —NR^(6g)R^(6h);

R^(6e) and R^(6f) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

R^(6g) and R^(6h) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of —NH₂, —NH(C₁₋₄alkyl),and hydroxyl;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl.—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A;

R^(9a) and R^(9b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one ormore halo atoms;

Het² represents

n1 represents 1 or 2;

n2 represents 1 or 2;

R⁸ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one ormore halo atoms;

R^(5h) represents hydrogen or C₁₋₄alkyl;

Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or6-membered saturated heterocyclyl containing at least one heteroatomeach independently selected from O, S, S(═O)_(p) and N; said cyclobutyl,cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclylis optionally substituted with one or two C₁₋₄alkyl substituents, withone C₁₋₄alkyl and one hydroxy substituent, or with one hydroxysubstituent;

p represents 1 or 2;

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³;

L represents —CHR^(1a)—X—;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl;

R² represents

R³ represents —(C═O)H, —(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b);

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —S(═O)₂—NH₂,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂—C₃₋₆cycloalkyl,

C₁₋₄alkyl substituted with one or more halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, —S(═O)₂—C₁₋₄alkyl,—O—C₁₋₄alkyl-NH₂, —O—C₁₋₄alkyl-NH(C₁₋₄alkyl),—O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen, cyano, C₁₋₄alkyl, halo, and —O—C₁₋₄alkyl;

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein

Y represents CR³;

L represents —CHR^(1a)—X—;

X represents NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1b) represents hydrogen or C₁₋₄alkyl; in particular hydrogen;

R² represents

R³ represents —(C═O)—NR^(5a)R^(5b);

R^(5a) and R^(5b) each independently are selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyl substituted with one ormore halo atoms, and

C₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl and —O—C₁₋₄alkyl;

R^(4a), R^(4b) and R^(4c) each independently are selected from the groupconsisting of hydrogen and halo;

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(6b), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

Het¹ represents a monocyclic 4-, 5-, 6- or 7-membered saturated orpartially saturated heterocyclyl containing at least one heteroatom eachindependently selected from O, S, S(═O)_(p) and N;

each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R^(1a) represents C₁₋₄alkyl, orC₁₋₄alkyl substituted with one —OH.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R^(1a) represents C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R^(1b) is always taken togetherwith R^(1a) or R^(1c) to form —(CH₂)₃—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein

Y represents CR³;

L represents —CHR^(1a)—X— or —X—CHR^(1c)—;

X represents NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₃—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein

Y represents CR³;

L represents —CHR^(1a)—X— or —X—CHR^(1c)—;

X represents NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Y represents CR³.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein

Y represents CR³;

R³ represents —(C═O)—NR^(5a)R^(5b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Y represents N.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein L represents —CHR^(1a)—X— or—X—CHR^(1c)—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein X represents NR^(1b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R^(5c) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R^(1b) is not taken together withR^(1a) or R^(1c).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ represents a monocyclic 4-,5-, 6- or 7-membered saturated or partially saturated heterocyclylcontaining at least one heteroatom each independently selected from O,S, S(═O)_(p) and N; each optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo, —NR^(9a)R^(9b) C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄ alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ represents a bicyclic 8-, 9-or 10-membered saturated or partially saturated heterocyclyl containingat least one heteroatom each independently selected from O, S, S(═O)_(p)and N; each optionally substituted with one or two substituents eachindependently selected from the group consisting of halo, —NR^(9a)R^(9b)C₁₋₄alkyl, —(C═O)—OR^(5h), —S(═O)₂—C₁₋₆alkyl,—C₁₋₄alkyl-S(═O)₂—C₁₋₆alkyl, hydroxyl, —O—C₁₋₄alkyl, cyano, C₁₋₄alkylsubstituted with one or more halo atoms, and C₁₋₄alkyl substituted withone substituent selected from the group consisting of hydroxyl, —NH₂,—NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂; or two substituents on the samecarbon atom of said heterocyclyl are taken together to form togetherwith the common carbon atom to which they are attached Ring A. In anembodiment, the present invention relates to those compounds of Formula(I) and the N-oxides, the pharmaceutically acceptable addition salts,and the solvates thereof, or any subgroup thereof as mentioned in any ofthe other embodiments, wherein Het¹ represents a monocyclic 4-, 5-, 6-or 7-membered saturated or partially saturated heterocyclyl containingat least one heteroatom each independently selected from O, S, S(═O)_(p)and N; wherein two substituents on the same carbon atom of saidheterocyclyl are taken together to form together with the common carbonatom to which they are attached Ring A.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein L represents —CH(CH₃)—NH—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein L represents

(R stereochemistry).

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ as defined in any of theother embodiments is attached to the remainder of the molecule via aN-atom.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ is piperazin-1-yl optionallysubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ is piperazin-1-yl substitutedwith two C₁₋₄alkyl substituents.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein Het¹ is piperazin-1-yl substitutedwith one C₁₋₄alkyl substituent in position 3 and one C₁₋₄alkylsubstituent in position 5.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² represents

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² represents

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² represents

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² representing

is limited to

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² representing

is limited to

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R² represents

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R³ represents —(C═O)H,—(C═O)—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b), —(C═O)—OR^(5c), —C(═O)—Het¹,—C(═O)—NH—Het², C₁₋₄alkyl, —CH═N—OH, —CH(OH)—CH₂—NR^(5d)R^(5e),—CH(OH)—CH₂—Het¹, —CH(OH)—C₁₋₄alkyl, —C(OH)(C₁₋₄alkyl)₂, halo, or R³represents C₁₋₄alkyl substituted with one substituent selected from thegroup consisting of hydroxyl, fluoro, —NR^(5f)R^(5g), Het¹,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl, —O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar,

—O—C₁₋₄alkyl-OH, and —O—C₁₋₄alkyl-NH₂.

In an embodiment, the present invention relates to those compounds ofFormula (I) and the N-oxides, the pharmaceutically acceptable additionsalts, and the solvates thereof, or any subgroup thereof as mentioned inany of the other embodiments, wherein R³ is other than R⁷.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compounds 12, 14, 39, 117, 158, 184 and 276, tautomers andstereoisomeric forms thereof,

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compounds 12, 14, 39, 117, 158, 184, 328, 211 and 276,tautomers and stereoisomeric forms thereof,

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 117, tautomers and stereoisomeric forms thereof,

and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 117.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 184, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 184.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 276, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 276.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 158, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 158.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 14, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 14.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 12, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 12.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 39, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 39.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 328, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 328.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of compound 211, tautomers and stereoisomeric forms thereof,and the N-oxides, the pharmaceutically acceptable addition salts, andthe solvates thereof.

In an embodiment the compound of Formula (I) is compound 211.

All possible combinations of the above-indicated embodiments areconsidered to be embraced within the scope of this invention.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections unless the context indicatesotherwise, references to Formula (I) also include all other sub-groupsand examples thereof as defined herein.

The general preparation of some typical examples of the compounds ofFormula (I) is described hereunder and in the specific examples, and aregenerally prepared from starting materials which are either commerciallyavailable or prepared by standard synthetic processes commonly used bythose skilled in the art. The following schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention. For example, the skilled person will realizethat some of the general schemes wherein Y is Y¹ may, dependent on thereaction conditions, also apply for cases wherein Y represents—(C═O)—O—H or C₁₋₄alkyl substituted with OH.

Alternatively, compounds of the present invention may also be preparedby analogous reaction protocols as described in the general schemesbelow, combined with standard synthetic processes commonly used by thoseskilled in the art of organic chemistry.

The skilled person will realize that in the reactions described in theSchemes, although this is not always explicitly shown, it may benecessary to protect reactive functional groups (for example hydroxy,amino, or carboxy groups) where these are desired in the final product,to avoid their unwanted participation in the reactions. Conventionalprotecting groups can be used in accordance with standard practice. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art. This is illustrated in the specificexamples. For example, a skilled person will realize that e.g.preparation of compound 17 according to Scheme 1 requires cleavage ofthe tert-butoxycarbonyl (Boc) in acidic media such as for examplehydrochloric acid 4N in acetonitrile at 0° C. or room temperature. Forexample compound 244 is obtained after cleavage of thetert-butyldimethylsilyl in the presence of tetrabutylammonium Fluoride(1M in tetrahydrofuran) in tetrahydrofuran at room temperature. Forexample compound 79 is prepared according to Scheme 3 from compound 78by a palladium catalyzed amination reaction usingA-boc-1,2-diaminoethane followed by cleavage of the tert-butoxy carbonyl(Boc) with trifluoroactic acid as the acid source.

The skilled person will realize that in the reactions described in theSchemes, it may be advisable or necessary to perform the reaction underan inert atmosphere, such as for example under N₂-gas atmosphere.

It will be apparent for the skilled person that it may be necessary tocool the reaction mixture before reaction work-up (refers to the seriesof manipulations required to isolate and purify the product(s) of achemical reaction such as for example quenching, column chromatography,extraction).

The skilled person will realize that heating the reaction mixture understirring may enhance the reaction outcome. In some reactions microwaveheating may be used instead of conventional heating to shorten theoverall reaction time. The skilled person will realize that anothersequence of the chemical reactions shown in the Schemes below, may alsoresult in the desired compound of formula (I). The skilled person willrealize that intermediates and final compounds shown in the schemesbelow may be further functionalized according to methods well-known bythe person skilled in the art.

In general, compounds of formula (I) wherein L is defined as shown inscheme 1 and Y is Y¹ being N or CR³ wherein R³ is defined as —C₁₋₄alkyl,—(C═O)—O—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹ or halo, saidcompounds being represented by formula (Ia) can be prepared according tothe following reaction Scheme 1 wherein PG¹ is a protecting group suchas for example a tert-Butyloxycarbonyl (Boc) and halo² is defined as Cl,Br or I. All other variables in Scheme 1 are defined according to thescope of the present invention.

In Scheme 1, the following reaction conditions apply:

1: in the presence of a suitable acid such as for example hydrochloricacid (HCl) or trifluoroacetic acid (TFA), a suitable solvent such as forexample dichloromethane (DCM), at a suitable temperature such as roomtemperature;

2: in the presence of a suitable catalyst such as for example palladiumacetate (Pd(OAc)₂) or tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃), a suitable ligand such as for example Xanthphos or2-(di-tert-butylphosphino)biphenyl a suitable base such as for examplecesium carbonate or sodium tert-butoxide, a suitable solvent such as forexample 1,4-dioxane, at a suitable temperature such as 100° C., in asealed vessel;

In general, compounds of formula (I) wherein L is defined as shown inscheme 2 and Y is Y¹ being N or CR³ wherein R³ is defined as —C₁₋₄alkyl,—(C═O)—O—C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹ or halo, andR^(1a) is defined as C₁₋₄alkyl, said compounds being represented byformula (Ib) and (Ic) can be prepared according to the followingreaction Scheme 2 wherein halo¹ is defined as Cl, Br and I, and halo³ isdefined as Cl or Br. ‘n-Bu’ means n-butyl. All other variables in Scheme2 are defined according to the scope of the present invention.

In Scheme 2, the following reaction conditions apply:

1: In case of reagent (IVa), in the presence of a suitable catalyst suchas for example dichlorobis(triphenylphosphine) palladium (II) ortetrakis(triphenylphosphine)palladium(0) (Pd(Ph₃)₄), a suitable solventsuch as for example 1,4-dioxane, at a suitable temperature such as 100°C. in a sealed or an open vessel; Then, in the presence of a suitableacid such as for example aqueous HCl, at a suitable temperature such asroom temperature;

In case of reagent (IVb), in the presence of a suitable catalyst such asfor example Pd(OAc)₂, a suitable ligand such as for example1,3-Bis(diphenylphosphino)propane (DPPP), a suitable base such as forexample triethylamine, a suitable solvent such as for exampledimethylsulfoxide, at a suitable temperature such as 100° C.; Then, inthe presence of a suitable acid such as for example HCl, at a suitabletemperature such as 0° C.;

2: in the presence of a suitable reducing reagent such as for examplesodium borohydride, a suitable solvent such as for example a mixture ofmethanol and dichloromethane, at a suitable temperature such as roomtemperature, in the presence or not of a suitable additive such as forexample cerium (III) chloride;

3: in the presence of a suitable halogenating reagent such as forexample phosphorous tribromide or thionyl chloride, a suitable solventsuch as for example dichloromethane, at a suitable temperature such asfor example 10° C. or room temperature;

4: in the presence of a suitable solvent such as for example N,N-dimethylformamide, at a suitable temperature such as for example 50 or60° C., in a sealed vessel;

5: in the presence of a suitable reagent such as for exampledi-tert-butyl azodicarboxylate, a suitable phosphine such as for exampletriphenylphosphine, a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example roomtemperature;

6: in the presence of a suitable reagent such as for example hydrazinemonohydrate, a suitable solvent such as for example ethanol, at asuitable temperature such as for example 80° C.;

7: in the presence of a suitable catalyst such as for examplechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (Brettphos precatalyst first gen),a suitable base such as for example cesium carbonate, a suitable solventsuch as for example 2-methyl-2-butanol, at a suitable temperature suchas 100° C., in a sealed vessel.

In general, compounds of formula (I) wherein

L is defined as shown in scheme 3;

Y is Y¹ being N or CR³ wherein R³ is defined as —C₁₋₄alkyl, —(C═O)—O—C₁₋₄alkyl, —(C═O)— NR^(5a)R^(5b), —C(═O)—Het¹ or halo;

R^(1a) is defined as C₁₋₄alkyl or hydrogen for step 1 and 2, and isdefined according to the scope of the present invention for step 3);

said compounds being represented by formula (Id) can be preparedaccording to the following reaction Scheme 3 wherein halo¹ is defined asCl, Br or I and halo³ is defined as Cl or Br. All other variables inScheme 3 are defined according to the scope of the present invention.

In Scheme 3, the following reaction conditions apply:

1: in the presence of a suitable halogenating reagent such as forexample phosphorous tribromide or thionyl chloride, a suitable solventsuch as for example dichloromethane, at a suitable temperature such asfor example 10° C. or room temperature;

2: in the presence of a suitable solvent such as for example N,N-dimethylformamide, at a suitable temperature such as for example 50 or60° C., in a sealed vessel;

3: in the presence of a suitable reagent such as for exampledi-tert-butylazodicarboxylate, a suitable phosphine such as for exampletriphenylphosphine, a solvent such as for example tetrahydrofuran, at asuitable temperature such as for example room temperature;

Alternatively, in the presence of a suitable reagent such as for examplecyanoethylenetributylphosphorane, a solvent such as for example toluene,at a suitable temperature such as for example 60° C., in a sealedvessel.

In general, compounds of formula (I) wherein

L is defined as shown in scheme 4;

Y is Y¹ being N or CR³ wherein R³ is defined as —C₁₋₄alkyl, —(C═O)—O—C₁₋₄alkyl, —(C═O)— NR^(5a)R^(5b), —C(═O)—Het¹ or halo;

R^(1a) is defined as C₁₋₄alkyl or hydrogen;

said compounds being represented by formula (Ie), can be preparedaccording to the following reaction Scheme 4 wherein halo³ is defined asCl or Br. All other variables in Scheme 4 are defined according to thescope of the present invention.

In Scheme 4, the following reaction conditions apply:

1: in the presence of a suitable solvent such as for example N,Y-dimethyl formamide, at a suitable temperature such as for example 50or 60° C., in a sealed vessel.

In general, compounds of formula (I) wherein L is defined as shown inscheme 5 and Y is Y¹ being N or CR³ wherein R³ is defined as —C₁₋₄alkyl,—(C═O)—O— C₁₋₄alkyl, —(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹ or halo, saidcompounds being represented by formula (If) can be prepared according tothe following reaction Scheme 5 wherein halo¹ is defined as Cl, Br or I,W¹ is a leaving group such as for example Cl, Br or I, and n is 0, 1 or2. Moreover R^(5a) and R^(5b) are other than hydrogen for the purpose ofScheme 5. All other variables in Scheme 5 are defined according to thescope of the present invention.

In Scheme 5, the following reaction conditions apply:

1: in the presence of a suitable catalyst such as for examplechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (Brettphos precatalyst first gen),with or without a suitable ligand such as for example2-dicyclohexylphosphino-2,6′-diisopropoxy-1,1′-biphenyl, a suitable basesuch as for example cesium carbonate, a suitable solvent such as forexample tert-amyl alcohol (2-methyl-2-butanol) or toluene, at a suitabletemperature such as 100° C., in a sealed vessel;

2: in the presence of a suitable catalyst such as for examplechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (Brettphos precatalyst first gen)or palladium acetate, with or without a suitable ligand such as forexample 2-dicyclohexylphosphino-2,6′-diisopropoxy-1,1′-biphenyl or4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, a suitable base such asfor example cesium carbonate, a suitable solvent such as for exampletert-amyl alcohol, toluene or dioxane, at a suitable temperature rangedfrom 80 to 100° C., in a sealed vessel;

3: in the presence of a suitable deprotonating agent such as for examplesodium hydride, a suitable solvent such as for exampledimethylformamide, at a suitable temperature such as for example roomtemperature.

A subgroup of the Intermediates of formula (II) used in the above Scheme1, hereby named Intermediates of formula (II-1) wherein L is limitedaccording to scheme 6 and Y is Y^(1a) being N, —C—C₁₋₄alkyl,—C—(C═O)—O—C₁₋₄alkyl and C₁₋₄alkyl can be prepared according to thefollowing reaction Scheme 6 wherein PG¹ is a protecting group such asfor example a Boc, and halo² is defined as Cl, Br or I. All othervariables in Scheme 6 are defined according to the scope of the presentinvention.

In Scheme 6, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for example2,2-dihydroxy acetic acid, a suitable solvent such as for example amixture of water and methanol, at a suitable temperature such as roomtemperature;

Alternatively, in the presence of a suitable reagent such as for examplean ethyl glyoxalate solution in toluene, a suitable solvent such as forexample ethanol, at a suitable temperature such as solvent reflux;

2: in the presence of a suitable chlorinating reagent such as forexample phosphoryl trichloride (POCh), at a suitable temperature such as80° C.;

3: in the presence of a suitable coupling reagent such as for examplephosphoryl bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, asuitable base such as for example triethylamine, a suitable solvent suchas for example tetrahydrofuran, at a suitable temperature such as roomtemperature;

4: in case of an intermediate of formula (XXI): in the presence of asuitable solvent such as for example tetrahydrofuran, at a suitabletemperature such as solvent reflux; in case of an intermediate offormula (XXII) or in case of an intermediate of formula

-   -   (XXIII): in the presence of a suitable catalyst such as for        example [1,1′-Bis(diphenylphosphino)ferrocene]        dichloropalladium(II), complex with dichloromethane, suitable        base such as for example potassium phosphate, a suitable solvent        such as for example 1,4-dioxane, at a suitable temperature such        as for example 80° C., in a sealed vessel;

5: in the presence of a suitable catalyst such as for example Pd(OAc)₂,a suitable phosphine such as for example triphenylphosphine, a suitablebase such as for example potassium carbonate, a suitable solvent such asfor example N, N-dimethylformamide or 1,4-dioxane, at a suitabletemperature such as for example 100° C., in a sealed vessel;

6: in the presence of hydrogen, a suitable catalyst such as for exampleplatinum (IV) oxide, a suitable solvent such as for example methanol, ata suitable temperature such as for example room temperature;

7: in the presence of a suitable oxidative reagent such as for examplemanganese oxide, a suitable solvent such as for example dichloromethane,at a suitable temperature such as for example room temperature.

In general, compounds of formula (I) wherein L is L¹ being —CHR^(1a)—X—or —X—CHR^(1c)—; and Y is Y^(a) being CR³ wherein R³ is defined as—COOH, —CH₂OH, —(C═O)H, —CH(OH)—CH₂—NR^(5d)R^(5e), —CH(OH)—CH₂—Het¹,—(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹, —CH₂—NR^(5f)R^(5g) or —CH₂—Het¹, saidcompounds being represented respectively by compounds of formula (Ii),(Ij), (Ik), (Il), (Im), (Iad), I(ae), I(an) and I(ao), can be preparedaccording to the following reaction Scheme 7.

All other variables in Scheme 7 are defined according to the scope ofthe present invention.

In Scheme 7, the following reaction conditions apply:

1: in the presence of a suitable base such as for example lithiumhydroxide monohydrate or sodium carbonate, a suitable solvent such asfor example a mixture of water and tetrahydrofuran or a mixture ofwater, methanol and tetrahydrofuran, at a suitable temperature such asfor example 50° C. or room temperature;

2: in the presence of a suitable coupling reagent such as for exampleN,N,N′,N′-Tetramethyl-<9-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) or 1,1′-carbonyldiimidazole, asuitable base such as for example diisopropylethylamine, triethylamineor 1,8-diazabicyclo[5.4.0]undec-7-ene, a suitable solvent such as forexample A, A-di methyl formamide or methyltetrahydofuran, at a suitabletemperature such as for example room temperature;

3: in the presence of a suitable reducing reagent such as for examplediisobutylaluminium hydride, a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example −70° C.;

4: in the presence of a suitable coupling reagent such as for exampleHBTU, COMU, HATU or 1,1′-carbonyldiimidazole, a suitable base such asfor example diisopropylethylamine, triethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene, a suitable solvent such as forexample N. A-di methyl formamide or methyltetrahydofuran, at a suitabletemperature such as for example room temperature;

5: in the presence of a suitable oxidative reagent such as for examplemanganese dioxide, a suitable solvent such as for exampledichloromethane, at a suitable temperature such as for example roomtemperature;

6: in the presence of a suitable reagent such as for exampletrimethylsulfonium iodide, a suitable deprotonating reagent such as forexample sodium hydride, a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 70° C.;

7: in the presence of a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 100° C.,in a sealed vessel;

8: in the presence of a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 100° C.,in a sealed vessel;

9: in the presence of a suitable reducing agent such as for examplesodium borohydride, eventually a suitable base such as for examplesodium acetate, in a suitable solvent such as for example methanol at asuitable temperature such as room temperature.

In general, compounds of formula (I) wherein L is L³ defined as—CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-, or—CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)- and Y is defined as CR³ and R³ is definedas —(C═O)-NR^(5a)R^(5b), said compounds being represented by formula(In), can be prepared according to the following reaction Scheme 8wherein halo¹ is defined as Cl, Br or I. All other variables in Scheme 8are defined as above or according to the scope of the present invention.

In Scheme 8, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for exampleBis(pinacolato)diboron, a suitable catalyst such as for example[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), a suitablebase such as for example potassium acetate, a suitable solvent such asfor example 1,4-dioxane, at a suitable temperature such as for example100° C.;

2: in the presence of a suitable reagent such as for example sodiumperiodate, a suitable acid such as for example hydrochloric acid, asuitable solvent such as for example a mixture of water andtetrahydrofuran, at a suitable temperature such as for example roomtemperature;

3: in the presence of a suitable reagent such as for exampleN-tosylhydrazine, a suitable base such as for example potassiumcarbonate, a suitable solvent such as for example 1,4-dioxane, at asuitable temperature such as for example ranged between 80° C., and 110°C.

In general, compounds of formula (I) wherein L is L² being—CH(C₁₋₄alkyl)-CH₂—, —CH₂—CH(C₁₋₄alkyl)-, —CH(C₁₋₄alkyl)-CH(C₁₋₄alkyl)-,CHR^(1a)—X—, or —X—CHR^(1c)—; and wherein Y is Y² being CR³ and R³ isdefined as —CH(OH)C₁₋₄alkyl or —C(OH)(C₁₋₄alkyl)₂, said compounds beingrespectively represented by formula (Io) and (Ip), can be preparedaccording to the following reaction Scheme 9.

For the purpose of Scheme 9, halo⁴ is defined as Cl or Br;

X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1b) represents C₁₋₄alkyl

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂— or —(CH₂)₄—.

All other variables in Scheme 9 are defined according to the scope ofthe present invention.

In Scheme 9, the following reaction conditions apply:

1: in the presence of a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 10° C.;

2: in the presence of a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 10° C.;

3: in the presence of a suitable oxidative reagent such as for examplemanganese dioxide, a suitable solvent such as for exampledichloromethane, at a suitable temperature such as room temperature;

4: in the presence of a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 10° C.

In general, compounds of formula (I) wherein Y is Y³ being CR³ and R³ isrestricted to R^(7a) being defined as

said compounds being represented by formula (Iq), can be preparedaccording to the following reaction Scheme wherein halo⁵ is defined asCl, Br or I. All other variables in Scheme 10 are defined according tothe scope of the present invention.

In Scheme 10, the following reaction conditions apply:

1: in the presence of a suitable catalyst such as for example1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane, a suitable solvent such as for example tetrahydrofuran,at a suitable temperature such as for example 95° C., and eventuallyfollowed by protective groups cleavage using state of the art methods.

In general, compounds of formula (I) wherein Y is Y⁴ being CR³ and R³ isdefined as CH₂ substituted with one substituent selected from the groupconsisting of fluoro, —NR^(5f)R^(5g), Het¹, —O—C₁₋₄alkyl-OH, and—O—C₁₋₄alkyl-NH₂, said compounds being respectively represented byformula (Ir), (Is), (It), (Iu), (Iv) and (Iw) can be prepared accordingto the following reaction Scheme 11 wherein halo⁶ is defined as Cl orBr, W² as a leaving group such as for example Cl or Br and PG² aprotective group such as for example a tert-Butyldimethylsilyl (TBDMS).All other variables in Scheme 11 are defined according to the scope ofthe present invention.

In Scheme 11, the following reaction conditions apply:

1: in the presence of a suitable halogenating reagent such as forexample thionyl chloride, in the presence of a suitable solvent such asfor example dichloromethane, at a suitable temperature such as forexample room temperature;

2: in the presence of a suitable solvent such as for exampleacetonitrile, at a suitable temperature such as for example 80° C.;

3: in the presence of a suitable deprotonating reagent such as forexample sodium hydride, a suitable solvent such as for exampleN,N-dimethylformamide, at a suitable temperature such as for exampleroom temperature;

4: in the presence of a suitable fluorinating reagent such as forexample diethylaminosulfur trifluoride, a suitable solvent such as forexample dichloromethane, at a suitable temperature such as for exampleroom temperature;

5: in the presence of a suitable solvent such as for exampleacetonitrile, at a suitable temperature such as for example 80° C.;

6: in the presence of a suitable acid such as for exampletrifluoroacetic acid, a suitable solvent such as for example methanol,at a suitable temperature such as room temperature;

7: in the presence of a suitable reagent such as for exampledi-tert-butyl azodicarboxylate, a suitable phosphine such as for exampletriphenylphosphine, a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example roomtemperature;

8: in the presence of a suitable reagent such as for example hydrazinemonohydrate, a suitable solvent such as for example ethanol, at asuitable temperature such as for example 80° C.

Compounds of formula (I) wherein Y is Y⁵ being CR³ and R³ is definedC₂₋₄alkyl substituted with one substituent selected from the groupconsisting of fluoro, —NR^(5f)R^(5g), Het¹, —O—C₁₋₄alkyl-OH, and—O—C₁₋₄alkyl-NH₂ can be prepared from the aldehyde I(k) using couplingsuch as Wittig or Homer Emmons olefinaltion with the appropriatecoupling partner followed by reduction of the double bond.

In general, compounds of formula (I) wherein Y is Y⁶ being CR³ and R³ isdefined as C₁₋₄alkyl substituted with one substituent selected from thegroup consisting of —O—(C═O)—CH(NH₂)—C₁₋₄alky 1,—O—(C═O)—CH(NH₂)—C₁₋₄alkyl-Ar and

said compounds being respectively represented by formula (Ix), (Iy) and(Iz) can be prepared according to the following reaction Scheme 12wherein PG³ is defined as a protective group such for example Boc. Allother variables in Scheme 12 are defined as above or according to thescope of the present invention.

In Scheme 12, the following reaction conditions apply:

1: in the presence of a suitable coupling reagent such as for example1-[bis(dimethylamino)methylene]-1H-1,2,3-Triazolo[4,5-b]pyridinium,3-oxide, a suitable additive such as for example dimethylaminopyridine,a suitable base such as for example diisopropylethylamine, and in asuitable solvent such as for example of DMF;

2: in the presence of an acide such as for example trifluoroacetic acidor hydrogen chloride in a suitable solvent such as for exampledichloromethane or methanol. Alternatively, in the presence of palladiumon charcoal, in a suitable solvent such as methanol under an atmosphereof hydrogen.

Intermediates of formula (XIXaa) when Y is Y⁷ being CR³ wherein R³ isdefined as —(C═O)—O—C₁₋₄alkyl used in the above Scheme 6 canalternatively be prepared according to the following reaction scheme 13wherein halo¹ is defined as above. All other variables in Scheme 13 aredefined according to the scope of the present invention.

In Scheme 13, the following reaction conditions apply:

1: in the presence of a suitable base such as for examplediisopropylethylamine, a suitable solvent such as for exampledimethylacetamide, at a suitable temperature such as room temperature;

2: in the presence of a suitable reducing reagent such as for exampleTin(II) chloride dihydrate, a suitable solvent such as for exampleethanol, at a suitable temperature such as 80° C.;

3: in the presence of a suitable oxidative reagent such as for examplemanganese dioxide, a suitable solvent such as for exampledichloromethane at a suitable temperature such as room temperature.

In general, compounds of formula (I), wherein Y is Y₁ being N or CR³wherein R³ is defined as —C₁₋₄alkyl, —(C═O)—O—C₁₋₄alkyl,—(C═O)—O—NR^(5a)R^(5b), —C(═O)—Het¹ or halo, said compounds beingrepresented by formula (Ic), already described in scheme 2, canalternatively be prepared according to the following reaction Scheme 14.All variables in Scheme 14 are defined according to the scope of thepresent invention.

In Scheme 14, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for examplecyanomethylenetributylphosphorane, a suitable solvent such as forexample toluene, at a suitable temperature such as for example 60° C.,optionally in a sealed vessel;

Alternatively, in the presence of a suitable reagent such as for examplediisopropylazodicarboxylate, a suitable phosphine such as for exampletributylphosphine, in a suitable solvent such as for exampletetrahydrofuran, keeping temperature at 0° C. during reagents additionand then, increase to 30° C.;

2: in the presence of a suitable acid such as for example thioglycolicacid, a suitable base such as for example1,8-diazabicyclo(5.4.0)undec-7-ene, a suitable solvent such as forexample acetonitrile, at a suitable temperature such as roomtemperature.

Intermediates of formula (LIII) and (LIV), wherein Y is Y⁸ being CR³wherein R³ is defined as —(C═O)—O— NR^(5a)R^(5b), —C(═O)—Het¹, which maybe used as starting material in the above Schemes 2 and 5 can beprepared according to the following reaction Scheme 15. All variables inScheme 15 are defined as before or according to the scope of the presentinvention.

In Scheme 15, the following reaction conditions apply:

1: in the presence of a suitable base such as for example lithiumhydroxide monohydrate or sodium hydroxide, a suitable solvent such asfor example a mixture of water and tetrahydrofuran or a mixture ofwater, ethanol and tetrahydrofuran, at a suitable temperature such asroom temperature;

2: in the presence of a suitable coupling reagent such as for exampleHBTU or 1,1′-carbonyldiimidazole, a suitable base such as for example²diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, a suitablesolvent such as for example N,N-dimethylformamide ormethyltetrahydofuran, at a suitable temperature such as for example roomtemperature.

In general, compounds of formula (I) wherein Y is Y⁹ being CR³ and R³ isdefined as —CH₂—NH₂, said compounds being represented by formula (Iaa)can be prepared according to the following reaction Scheme 16. Allvariables in Scheme 16 are defined as above or according to the scope ofthe present invention.

In Scheme 16, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for exampledi-tert-butyl azodicarboxylate, a suitable phosphine such as for exampletriphenylphosphine, a suitable solvent such as for exampletetrahydrofuran, at a suitable temperature such as for example 40° C.;

2: in the presence of a suitable reagent such as for example hydrazinemonohydrate, a suitable solvent such as for example methanol, at asuitable temperature such as for example 70° C.

Intermediates of formula (LIX) (subgroup of intermediates of formula(XI) used in the above Scheme 2) wherein Y is Y¹⁰ being CR³ wherein R³is defined as —(C═O)—O—C₁₋₄alkyl, can be prepared in enantiomericallypure form according to the following reaction Scheme 17. All variablesin Scheme 17 are defined according to the scope of the presentinvention.

In Scheme 17, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for example titanium(IV) ethoxide, a suitable solvent such as for example tetrahydrofuran orcyclopentyl methyl ether, at a suitable temperature such as for exampleroom temperature;

2: in the presence of a suitable reducing reagent such as for examplesodium cyanoborohydride, a suitable acid such as for example aceticacid, a suitable solvent such as for example a mixture of methanol anddichloromethane, at a suitable temperature such as for example −15° C.;

3: in the presence of a suitable oxidative reagent such as for examplemanganese dioxide, a suitable solvent such as for exampledichloromethane, at a suitable temperature such as for example roomtemperature;

4: in the presence of a suitable acid such as for example hydrochloricacid, a suitable solvent such as for example a mixture of acetonitrileand 1,4-dioxane, at a suitable temperature such as for example roomtemperature.

Intermediates of formula (LXII) and (LXIII) (subgroups of intermediatesof formula (XI) used in the above Scheme 2) wherein Y is Y¹¹ being CR³wherein R³ is defined as —(C═O)—O— NR^(5a)R^(5b), can be preparedaccording to the following reaction Scheme 18. All variables in Scheme18 are defined according to the scope of the present invention.

In Scheme 18, the following reaction conditions apply:

1: in the presence of a suitable reagent such as for example titanium(IV) ethoxide, a suitable solvent such as for example tetrahydrofuran orcyclopentyl methyl ether, at a suitable temperature such as for exampleranged from room temperature to solvent reflux; then, in the presence ofa suitable reducing reagent such as for example sodium borohydride, at asuitable temperature such as for example ranged between −50° C. and roomtemperature;

2: in the presence of a suitable acid such as for example hydrochloricacid, a suitable solvent such as for example 1,4-dioxane, at a suitabletemperature such as for example room temperature.

In general, compounds of formula (I) wherein L is L¹ being —CHR^(1a)—X—or —X—CHR^(1c)—; and Y is Y¹² being CR³ wherein R³ is defined as

said compounds being represented respectively by formula (lab) and(lac), can be prepared according to the following reaction Scheme 19.

For the purpose of Scheme 19, X represents O, S, or NR^(1b);

R^(1a) represents C₁₋₄alkyl;

R^(1c) represents hydrogen or C₁₋₄alkyl;

R^(1b) represents hydrogen, C₁₋₄alkyl, —CH₂—C(═O)—NR^(6a)R^(6b), orC₁₋₄alkyl substituted with one substituent selected from the groupconsisting of hydroxyl, —O—C₁₋₄alkyl, and —NR^(6c)R^(6d);

or R^(1b) is taken together with R^(1a) or R^(1c) to form —(CH₂)₃—;

or R^(1b) is taken together with R^(1c) to form —(CH₂)₂— or —(CH₂)₄—.

All other variables in Scheme 19 are defined according to the scope ofthe present invention.

In Scheme 19, the following reaction conditions apply:

1: in the presence of a suitable coupling reagent such as for exampleHBTU or 1,1′-carbonyldiimidazole, a suitable base such as for examplediisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, a suitablesolvent such as for example N,N-dimethylformamide ormethyltetrahydofuran, at a suitable temperature such as for example roomtemperature;

2: in the presence of a suitable halogenating reagent such as forexample thionyl chlorine, a suitable solvent such as for exampledichloromethane, at a suitable temperature such as for example roomtemperature.

In general, compounds of formula (I) wherein Y is Y¹³ being CR³ whereinR³ is defined as —CH═N—OH, said compounds being respectively representedby formula (lam), can be prepared according to the following reactionScheme 20 wherein all other variables are defined according to the scopeof the present invention.

In Scheme 20, the following reaction conditions apply:

1: in the presence of a suitable solvent such as for example ethanol, ata suitable temperature such as for example 100° C.

In general, compounds of formula (I) wherein L is defined as —CH₂—X—;and Y is Y¹ being being N or CR³ wherein R³ is defined as —C₁₋₄alkyl,—(C═O)—O—C₁₋₄alkyl. —(C═O)—NR^(5a)R^(5b), —C(═O)—Het¹ or halo; saidcompounds being represented respectively by formula (Iba) and (lea), canbe prepared according to the following reaction Scheme 21.

All other variables in Scheme 21 are defined as above or according tothe scope of the present invention.

In Scheme 21, the following reaction conditions apply:

1: in the presence of a suitable catalyst such as for example[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, a suitable base such as for example potassiumphosphate, in a suitable solvent such as for example a mixture ofdioxane and water, at a suitable temperature such as 90° C., optionallyin a sealed reactor;

2: in the presence of a suitable oxidative agent such as for exampleosmium tetroxide and sodium periodate, in a suitable solvent such as forexample tetrahydrofuran;

3: in the presence of a suitable reducing reagent such as for examplesodium borohydride, a suitable solvent such as for example a mixture ofmethanol and dichloromethane, at a suitable temperature such as roomtemperature, in the presence or not of a suitable additive such as forexample cerium (III) chloride;

4: in the presence of molecular sieve 4 Å, in a suitable solvent such asfor example dichloromethane, optionally in a sealed reactor;

5: in the presence of a suitable halogenating reagent such as forexample phosphorous tribromide or thionyl chloride, a suitable solventsuch as for example dichloromethane, at a suitable temperature such asfor example 10° C. or room temperature;

6: in the presence of a suitable solvent such as for example N,N-dimethylformamide, at a suitable temperature such as for example 50 or60° C., in a sealed vessel;

7: in the presence of a suitable reducing agent such as for examplesodium triacetoxyborohydride, in a suitable solvent such as for exampledichloromethane;

In general, compounds of formula (I) wherein L is defined as—CH(C₁₋₄alkyl-OH)—X—, and Y is defined as CR³ wherein R³ is defined as—(C═O)—NR^(3a)R^(5b); said compounds being represented by formula I(ao),can be prepared according to the following reaction Scheme 22. All othervariables in Scheme 22 are defined as above or according to the scope ofthe present invention.

In Scheme 22, the following reaction conditions apply:

1: in a suitable solvent such as for example hexafluoroisopropanol.

In general, compounds of formula (I) wherein L is L¹ being —CHR^(1a)—X—or —X—CHR^(1c)—; and Y is Y^(a) being CR³ wherein R³ is defined as—(C═O)—NH—C₁₋₄alkyl-Het¹, —(C═O)—N(C₁₋₄alkyl)—C₁₋₄alkyl-Het¹,—CH₂—NHHet² or as —(C═O)—NH—C₁₋₄alkyl-Het², said compounds beingrepresented respectively by compounds of formula I(ap), I(aq), I(ar),and I(as), can be prepared according to the following reaction Scheme23.

All other variables in Scheme 23 are defined according to the scope ofthe present invention.

In Scheme 23, the following reaction conditions apply:

1: in the presence of a suitable coupling reagent such as for exampleN,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) or 1,1′-carbonyldiimidazole, asuitable base such as for example diisopropylethylamine, triethylamineor 1,8-diazabicyclo[5.4.0]undec-7-ene, a suitable solvent such as forexample A, A-di methyl formamide or methyltetrahydofuran, at a suitabletemperature such as for example room temperature.

A subgroup of the Intermediates of formula (VII) used in the aboveScheme 2, hereby named Intermediates of formula (VIIaa) wherein R² isrestricted to

and Y is restricted to —C—(C═O)—O—C₁₋₄alkyl can be prepared according tothe following reaction Scheme 24. All other variables in Scheme 24 aredefined according to the scope of the present invention.

In Scheme 24, the following reaction conditions apply:

1: in a suitable solvent such as for example toluene at a suitabletemperature such as reflux;

2: in the presence of a suitable chlorinating reagent such as forexample thionyl chloride, a suitable additive such as for exampledimethylformide, in a suitable solvent such as for example1,2-dichloroethane at a suitable temperature such as 80° C.;

3: in the presence of a suitable base such as for exampletrimethylamine, in a suitable solvent such as for example2-methyltetrahydrofuran;

4: in the presence of a suitable base such as for example1,8-Diazabicyclo[5.4.0]undec-7-ene, a suitable catalyst such as forexample palladium on carbon (Pd/C), in a suitable solvent such as forexample dichloromethane;

Then, after filtration of the catalyst, filtrate is treated with asuitable oxy dating agent such as manganese dioxide, at a suitabletemperature such as for example 30 to 40° C.;

5: in the presence of a suitable halogenating agent such as for exampledimethyldibromohydantoin, in a suitable solvent such as for exampledichloromethane at a suitable temperature such as for example 30 to 40°C.;

6: In case of reagent (IVa), in the presence of a suitable catalyst suchas for example dichlorobis(triphenylphosphine) palladium (II) or

tetrakis(triphenylphosphine)palladium(0) (Pd(Ph₃)₄), a suitable solventsuch as for example 1,4-dioxane, at a suitable temperature such as 100°C. in a sealed or an open vessel; Then, in the presence of a suitableacid such as for example aqueous HCl, at a suitable temperature such asroom temperature;

In case of reagent (IVb), in the presence of a suitable catalyst such asfor example Pd(OAc)₂, a suitable ligand such as for example1,3-Bis(diphenylphosphino)propane (DPPP), a suitable base such as forexample triethylamine, a suitable solvent such as for exampledimethylsulfoxide, at a suitable temperature such as 100° C.; Then, inthe presence of a suitable acid such as for example HCl, at a suitabletemperature such as 0° C.;

7: in the presence of an enantioselective reducting agent such as forexample (−)-B-chlorodiisopinocampheylborane, in a suitable solvent suchas for example dichloromethane, at a suitable temperature such as −35°C.

In all these preparations, the reaction products may be isolated fromthe reaction medium and, if necessary, further purified according tomethodologies generally known in the art such as, for example,extraction, crystallization, trituration and chromatography.

The chirally pure forms of the compounds of Formula (I) form a preferredgroup of compounds. It is therefore that the chirally pure forms of theintermediates and their salt forms are particularly useful in thepreparation of chirally pure compounds of Formula (I). Also enantiomericmixtures of the intermediates are useful in the preparation of compoundsof Formula (I) with the corresponding configuration.

Pharmacology

It has been found that the compounds of the present invention inhibitPI3Kβ kinase activity, and optionally also have PI3Kδ inhibitoryactivity.

It is therefore anticipated that the compounds according to the presentinvention or pharmaceutical compositions thereof may be useful fortreating or preventing, in particular treating, of diseases such ascancer, autoimmune disorders, cardiovascular diseases, inflammatorydiseases, neurodegenerative diseases, allergy, pancreatitis, asthma,multiorgan failure, kidney diseases, platelet aggregation, spermmotility, transplantation rejection, graft rejection, lung injuries andthe like; in particular cancer.

Because the pharmaceutically active compounds of the present inventionare active as PI3Kβ inhibitors, they exhibit therapeutic utility intreatment or prevention, in particular treatment, of susceptibleneoplasms, particularly those neoplasms that exhibit a PTEN deficiency.

As used herein, the phrase “PTEN deficient” or “PTEN deficiency” shalldescribe tumors with deficiencies of the tumor suppressor function ofPTEN (Phosphatase and Tensin Homolog). Such deficiency includes mutationin the PTEN gene, reduction or absence of PTEN proteins when compared toPTEN wild-type, or mutation or absence of other genes that causesuppression of PTEN function.

“Susceptible neoplasm” as used herein refers to neoplasms which aresusceptible to treatment by a kinase inhibitor and particularlyneoplasms that are susceptible to treatment by a PI3Kβ inhibitor.Neoplasms which have been associated with inappropriate activity of thePTEN phosphatase and particularly neoplasms which exhibit mutation ofPTEN, or mutation of an upstream activator of PI3Kβ kinase oroverexpression of an upstream activator of PI3Kβ kinase, and aretherefore susceptible to treatment with an PI3Kβ inhibitor, are known inthe art, and include both primary and metastatic tumors and cancers.According to an embodiment, description of the treatment of asusceptible neoplasm may be used interchangeably with description of thetreatment of a cancer.

According to one embodiment, “susceptible neoplasms” include but are notlimited to PTEN-deficient neoplasms listed as follows: brain (gliomas),glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease,Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer,colorectal cancer Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma,ependymoma, medulloblastoma, colon cancer, head and neck cancer, livercancer, kidney cancer, lung cancer, melanoma, squamous cell carcinoma,ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer,osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic Tcell leukemia, chronic myelogenous leukemia, chronic lymphocyticleukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acutemyelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblasticT cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantlecell leukemia, Multiple myeloma, Megakaryoblastic leukemia. Acutemegakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma,lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,neuroblastoma, bladder cancer, urothelial cancer, cervical cancer,vulval cancer, endometrial cancer, renal cancer, mesothelioma,esophageal cancer, salivary gland cancer, hepatocellular cancer, gastriccancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST(gastrointestinal stromal tumor), and testicular cancer.

According to an alternative embodiment, the term “susceptible neoplasm”includes and is limited to hormone refractory prostate cancer,non-small-cell lung cancer, endometrial cancer, gastric cancer,melanoma, head and neck cancer, breast cancer, including tripnegativebreast cancer, and glioma.

In an embodiment, the term “susceptible neoplasm” includes and islimited to prostate cancer, in particular hormone refractory prostatecancer.

The compounds of the present invention may also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy.

Hence the compounds of the present invention may be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2-nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogoues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

The invention relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, foruse as a medicament.

The invention also relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, foruse in the inhibition of PI3Kβ kinase activity and optionally also foruse in the inhibition of PI3Kδ.

The compounds of the present invention can be “anti-cancer agents”,which term also encompasses “anti-tumor cell growth agents” and“anti-neoplastic agents”.

The invention also relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, foruse in the treatment of diseases mentioned above.

The invention also relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, forthe treatment or prevention, in particular for the treatment, of saiddiseases.

The invention also relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, forthe treatment or prevention, in particular in the treatment, of PI3Kβmediated diseases or conditions.

The invention also relates to compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, forthe treatment or prevention, in particular in the treatment, of PI3Kβand optionally PI3Kδ mediated diseases or conditions.

The invention also relates to the use of compounds of Formula (I) andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament.

The invention also relates to the use of compounds of Formula (I) andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament for the inhibition ofPI3Kβ.

The invention also relates to the use of compounds of Formula (I) andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament for the inhibition of PI3Kβand optionally also for the inhibition of PI3Kδ.

The invention also relates to the use of compounds of Formula (I) andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament for the treatment orprevention, in particular for the treatment, of any one of the diseaseconditions mentioned hereinbefore.

The invention also relates to the use of compounds of Formula (I) andN-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, for the manufacture of a medicament for the treatment of anyone of the disease conditions mentioned hereinbefore.

The compounds of Formula (I) and N-oxides, pharmaceutically acceptableaddition salts, and solvates thereof, can be administered to mammals,preferably humans for the treatment or prevention of any one of thediseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I) and N-oxides,pharmaceutically acceptable addition salts, and solvates thereof, thereis provided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from any one of the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of an effective amountof a compound of Formula (I) or a N-oxide, a pharmaceutically acceptableaddition salt, or a solvate thereof, to warm-blooded animals, includinghumans.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg bodyweight, more in particular from 0.01 mg/kg to 25 mg/kg body weight,preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably fromabout 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1mg/kg body weight. The amount of a compound according to the presentinvention, also referred to here as the active ingredient, which isrequired to achieve a therapeutically effect will of course, vary oncase-by-case basis, for example with the particular compound, the routeof administration, the age and condition of the recipient, and theparticular disorder or disease being treated.

A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by knownprocedures using well known and readily available ingredients.

The compounds of the present invention, that can be suitable to treat orprevent cancer or cancer-related conditions, may be administered aloneor in combination with one or more additional therapeutic agents.Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of Formula (If a N-oxide, apharmaceutically acceptable addition salt, or a solvate thereof, and oneor more additional therapeutic agents, as well as administration of thecompound of Formula (I), a N-oxide, a pharmaceutically acceptableaddition salt, or a solvate thereof, and each additional therapeuticagents in its own separate pharmaceutical dosage formulation. Forexample, a compound of Formula (I), a N-oxide, a pharmaceuticallyacceptable addition salt, or a solvate thereof, and a therapeutic agentmay be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent may beadministered in separate oral dosage formulations.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.

Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and, asactive ingredient, a therapeutically effective amount of a compound ofFormula (I), a N-oxide, a pharmaceutically acceptable addition salt, ora solvate thereof.

The carrier or diluent must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. The compoundsaccording to the invention, in particular the compounds of Formula (I)and N-oxides, pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup or combination thereof may be formulated intovarious pharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound as the active ingredient iscombined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, inparticular, for administration orally, rectally, percutaneously, byparenteral injection or by inhalation. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed such as, for example, water, glycols, oils, alcohols andthe like in the case of oral liquid preparations such as suspensions,syrups, elixirs, emulsions and solutions; or solid carriers such asstarches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules and tablets.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit forms in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, for example, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable solutions containinga compound of Formula (I), a N-oxide, a pharmaceutically acceptableaddition salt, or a solvate thereof, may be formulated in an oil forprolonged action. Appropriate oils for this purpose are, for example,peanut oil, sesame oil, cottonseed oil, com oil, soybean oil, syntheticglycerol esters of long chain fatty acids and mixtures of these andother oils. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations that are intended tobe converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acidor base addition salts of compounds of Formula (I) due to theirincreased water solubility over the corresponding base or acid form, aremore suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) and N-oxides, pharmaceutically acceptable addition salts,and solvates thereof, in pharmaceutical compositions, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives,in particular hydroxy alkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of Formula (I), a N-oxide, a pharmaceuticallyacceptable addition salt, or a solvate thereof, and from 1 to 99.95% byweight, more preferably from 30 to 99.9% by weight, even more preferablyfrom 50 to 99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

As another aspect of the present invention, a combination of a compoundof the present invention with another anticancer agent is envisaged,especially for use as a medicine, more specifically for use in thetreatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        temozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoïden for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and anti angiogenic agents such as        Bcl-2 inhibitors for example YC 137, BFI 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifamib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MEN 0.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat;    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b;    -   MAPK inhibitors;    -   Retinoids for example alitretinoin, bexarotene, tretinoin;    -   Arsenic trioxide;    -   Asparaginase;    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone;    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate;    -   Thalidomide, lenalidomide;    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase;    -   BH3 mimetics for example ABT-737;    -   MEK inhibitors for example PD98059, AZD6244, CI-1040;    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g, darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin;    -   a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate;    -   Glycolysis inhibitors, such as 2-deoxyglucose;    -   mTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase        inhibitors; PI3K inhibitors and dual mTOR/PI3K inhibitors;    -   autophagy inhibitors, such as chloroquine and        hydroxy-chloroquine;    -   antibodies that re-activate the immune response to tumors, for        example nivolumab (anti-PD-1), lambrolizumab (anti-PD-1),        ipilimumab (anti-CTLA4), and MPDL3280A (anti-PD-L1).

The compounds of the invention can also be advantageously combined withanti-androgen therapies including androgen receptor antagonists andinhibitors of androgen biosynthesis in PTEN-negative prostate cancers.

The present invention further relates to a product containing as firstactive ingredient a compound according to the invention and as furtheractive ingredient one or more anticancer agents, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein. Theweight ratio of the compound according to the present invention and theone or more other anticancer agent(s) when given as a combination may bedetermined by the person skilled in the art. Said ratio and the exactdosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of Formula (I) and another anti cancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularity for cisplatin in a dosage ofabout 75 mg/m² and for carboplatin in about 300 mg/m² per course oftreatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of to 75 mg per square meter (mg/m²) of body surface area,for example 15 to 60 mg/m², particularly for doxorubicin in a dosage ofabout 40 to 75 mg/m², for daunorubicin in a dosage of about 25 to 45mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² per courseof treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment. These dosages may beadministered for example once, twice or more per course of treatment,which may be repeated for example every 7, 14, 21 or 28 days.

EXAMPLES

The following examples illustrate the present invention.

Hereinafter, the term ‘BOC’, ‘Boc’ or ‘boc’ means tert-butoxycarbonyl,means ‘DCM’ means dichloromethane, ‘MeOH’ means methanol, ‘EtOH’ meansethanol, ‘ACN’ means acetonitrile, ‘THF’ means tetrahydrofuran, ‘Me-THF’means methyltetrahydrofuran, ‘DMF’ means dimethylformamide, ‘EtOAc’means ethyl acetate, ‘H₂O’ means water, ‘DMA’ means dimethylacetamide,‘DME’ means ethylene glycol dimethyl ether, ‘Et₂O’ means diethyl ether,‘iPrOH’ means isopropanol, ‘K₂CO₃’ means potassium carbonate, ‘K₃PO₄’means potassium phosphate, ‘NH₄OH’ means ammonia aqueous solution,‘NaHCO₃’ means sodium bicarbonate, ‘NaOH’ means sodium hydroxide, ‘NaCl’means sodium chloride, ‘NH₄Cl’ means ammonium chloride, ‘Celite®’ meansdiatomaceous earth, ‘NMP’ means A-methylpyrrolidine, ‘LiCl’ meanslithium chloride, ‘NH₄HCO₃’ means ammonium bicarbonate, ‘KOAc’ meanspotassium acetate, ‘DIPEA’ means diisopropylethylamine, ‘iPrNH₂’ meansisopropylamine, ‘MgSO₄’ means magnesium sulfate, ‘Na₂SO₄’ means sodiumsulfate, ‘N₂’ means nitrogen, ‘HCl’ means hydrochloric acid, ‘quant.’means quantitative, ‘TFA’ means trifluoroacetic acid, ‘NaBH₄’ meanssodium borohydride, ‘LiAlH₄’ means lithium aluminium hydride, ‘MnO₂’means manganese(IV) oxide, ‘CO₂’ means carbon dioxide, ‘CO’ means carbonmonoxide, ‘SFC’ means supercritical fluid chromatography, ‘HBTU’ meansN,N,N′,N′-tetramethyl-<9-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate, O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, ‘TBAF’ means tetrabutylammonium fluoride, ‘PPh₃’means triphenylphosphine, ‘Pd(OAc)₂’ means palladium(II) acetate,‘Pd₂(dba)₃’ means tris(dibenzylideneacetone)dipalladium(0), ‘Pd(PPh₃)₄’means tetrakis(triphenylphosphine) palladium(0), ‘Pd.Cl₂(dppf).DCM’means dichloro [1,1′-bis(diphenylphosphino) ferrocene] palladium(II)dichloromethane adduct, ‘BrettPhos’ means2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,‘rt’ means room temperature, ‘OR’ means optical rotation, ‘BrettPhosPrecatalyst First Gen’ meanschloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), ‘Xantphos’ means4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, ‘de’ meansdiastereomeric excess, ‘ee’ or ‘e.e.’ means enantiomeric excess, ‘M.P.’means melting point, ‘DSC’ means differential scanning calorimetry, ‘K’means Kofler; ‘COMU’ means(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate, ‘HATU’ means1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, ‘MeTHF’ means 2-methyltetrahydrofuran.

When a stereocenter is indicated with ‘RS’ this means that a racemicmixture was obtained.

A. Preparation of the Intermediate Example A1

Preparation of Intermediate 1a and Intermediate 1b

At −40° C. 2,2-dihydroxy-acetic acid (85.61 g; 930 mmol) in H₂O (35 mL)was added dropwise to a solution of methyl-3,4-diamino-5-bromobenzoate(190 g; 775.28 mmol) in MeOH (2 L). Then, the reaction mixture wasallowed to warm to rt and stirred for 2 h. The solid was filtered,washed with Et₂O and dried under vacuum to give 214 g (98%) of a mixtureof two intermediates 1a and 1b (ratio ˜85/15 by ¹H NMR).

Alternative Pathway:

Ethyl glyoxalate solution (6.6 mL; 66.1 mmol; 50% in toluene) was addedto a solution of methyl-3,4-diamino-5-bromobenzoate (8.1 g; 33.05 mmol)in EtOH (150 mL). The reaction mixture was heated at reflux for 3 h. Themixture was cooled down to rt and the precipitate was filtered, washedwith diethylether and dried under vacuum to give 7.3 g (78%) of amixture of intermediates 1a and 1b.

Alternative Preparation of Intermediate 1a

Preparation of Intermediate 1c:

To a solution of methyl-3-bromo-5-fluoro-4-nitrobenzoate (2 g; 7.2 mmol)and glycine ethyl ester hydrochloride (1.1 g; 7.9 mmol) in DMA (20 mL)was added DIPEA (4.9 mL; 28.8 mmol) at rt. The mixture was stirred at rtfor 2 days. H₂O and EtOAc were added. The organic layer was extracted,dried over MgSO₄, filtered and evaporated to dryness under vacuum togive 3.3 g of crude intermediate. A purification was performed by silicagel chromatography (irregular SiOH 20-45 μm, 40 g, mobile phase:gradient from 100% heptane to 70% heptane, 30% EtOAc). The fractionscontaining the product were mixed and evaporated to give 2.1 g (81%) ofintermediate 1c.

Preparation of Intermediate 1d:

Intermediate 1c (200 mg; 0.55 mmol) was dissolved in EtOH (5 mL). Tin(II) chloride dihydrate (315 mg; 1.66 mmol) was added and the mixturewas heated at 80° C. for 4 hours and cooled down to rt. The resultingprecipitate was filtered, washed with EtOH and dried (vacuum, 60° C.,overnight) to give 90 mg (57%) of intermediate Id.

Preparation of Intermediate 1a:

To a solution of intermediate Id (90 mg; 0.32 mmol) in DCM (10 mL) wasadded manganese dioxide (110 mg; 1.26 mmol). The solution was stirred atrt for 2 hours. Manganese dioxide (55 mg; 0.63 mmol) was again added andthe solution was stirred overnight at rt. The mixture was filteredthrough a pad of Celite®, washed with DCM and the solvent was evaporatedto dryness to give 58 mg (65%) of intermediate 1a.

Preparation of Intermediate 2a and Intermediate 2b

A mixture of intermediate 1a and 1b (85/15) (25 g; 75.07 mmol) was addedslowly to POCl₃ (300 mL). The reaction mixture was heated at 80° C. for3 h. POCh was evaporated and DCM was added to the residue. The mixturewas poured into ice-water and extracted with DCM. The organic layer wasdried over MgSO₄, filtered and evaporated. The residue was purified bychromatography over silica gel (eluent: from 9/1 petroleum ether/EtOActo 4/1 petroleum ether/EtOAc). The pure fractions were collected and thesolvent was evaporated to give 17 g (75%) of intermediate 2a and 3 g(13%) of intermediate 2b.

Alternative Pathway:

A mixture of intermediate 1a (5 g; 17.7 mmol) in POCh (75 mL) was heatedat 80° C. for 4 h. The mixture was evaporated under vacuum and theresidue was taken-up in ice water and DCM. The mixture was slowlybasified with a 10% aqueous solution of K₂CO₃ and stirred at rt for 2 h.The aqueous layer was separated and extracted with DCM (2×). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedunder vacuum to give 4.89 g (92%, beige solid) of intermediate 2a.

Preparation of Intermediate 3a and Intermediate 3b

Triethylamine (95.4 mL; 660 mmol) was added to a mixture ofintermediates 1a and 1b (75 g; 132.47 mmol) (ratio 1a/1b undetermined)in THF (3 L) at 0° C. The reaction mixture was stirred at 0° C. for 10min. Then, morpholine (55.8 mL; 634 mmol) andbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (135.2 g; 290mmol) were added. The reaction mixture was stirred at rt for 12 h. Thesolvent was evaporated and the residue was washed with H₂O. The solid(yellow) was filtered, washed with ACN, then Et₂O and dried under vacuumto give 80 g (85%) of a mixture intermediates 3a and 3b (ratio ˜4/1 by1H NMR).

Alternative Pathway:

A mixture of intermediate 2a (3.3 g; 10.94 mmol) and morpholine (2.9 mL;32.83 mmol) in THF (50 mL) was heated at reflux for 3 h. The reactionmixture was cooled down to rt, then poured into ice-water and extractedwith EtOAc. The organic layer was washed with brine (2×), then water,dried over MgSO₄, filtered and evaporated to give 3.7 g (95%) ofintermediate 3a.

Alternative Preparation of Intermediate 3a:

Intermediate 186 was dissolved in dichloromethane (10 volumes) anddimethyl dibromohydantoin (0.8 equivalents) was added. After reacting at30-40° C. for 30 hours, the reaction mixture was washed with a saturatedsolution of ammonium chloride and the organic phase was concentrated togive intermediate 3a in quantitative yield (78 purity).

Preparation of Intermediate 4:

A solution of lithium hydroxide monohydrate (5.96 g; 141.97 mmol) in H₂O(60 mL) was added to a solution of a mixture of intermediates 3a and 3b(5/1) (10 g; 28.39 mmol) in THF (200 mL) at rt. The reaction mixture wasstirred at rt overnight. At 0° C., the solution was slowly acidifiedwith a 3N aqueous solution of HCl and stirred at 10° C. for 1 h. Theprecipitate was filtered, then washed with water and dried to give 7.4 g(70%. yellow solid. 91% of purity evaluated by LC/MS) of intermediate 4.M.P.: >260° C. (Kofler).

Alternative Pathway:

A 3M aqueous solution of NaOH (11.6 mL; 34.8 mmol) was added to amixture of intermediates 3a and 3b (4.08 g; 11.6 mmol) in EtOH (60 mL)and THF (60 mL). The reaction mixture was stirred at rt overnight andevaporated under vacuum. The residue was acidified with a 0.5 N aqueoussolution of HCl to give a precipitate. The solid was filtered off,washed with water, then diethylether and dried under vacuum to give 3.86g (99%, yellow solid) of intermediate 4.

Preparation of Intermediate 5:

At 10° C., HBTU (10.7 g; 28.1 mmol) was added portion wise to a mixtureof intermediate 4(9.5 g; 28.1 mmol), DIPEA (12.3 mL; 70.2 mmol) anddimethylamine (2M in THF) (21.1 mL; 42.1 mmol) in DMF (180 mL). Thereaction mixture was stirred at rt for the week-end. The solution waspoured into ice-water, extracted with EtOAc (2×). The organic layer waswashed with brine (2×), then dried over MgSO₄, filtered and evaporateduntil dryness. The residue was taken-up with diethylether, filtered anddried to give 9.5 g (93%) of intermediate 5.

Preparation of Intermediate 217

Intermediate 217 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 andN-(2-aminoethyl)-N-Methyl carbamic acid tert-butyl ester as startingmaterials (720 mg g; 49%).

Preparation of Intermediate 237

Intermediate 237 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 andN,N-Dimethylethylenediamine as starting materials (420 mg g; 70%).

Preparation of Intermediate 238

Intermediate 238 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 and2-Amino-Ethyl)isopropyl-carbamic acid tert-butylester as startingmaterials (5.6 g; 81%).

Example A2

Preparation of Intermediate 6a and Intermediate 6b

In a sealed vessel, a mixture of intermediate 5 (8 g; 21.9 mmol),N-boc-2,3-dihydro-1H-pyrrole (5.3 mL; 30.67 mmol) and K₂CO₃ (9.08 g;65.71 mmol) in anhydrous DMF (200 mL) was degazed under N₂. PPh₃ (1.15g; 4.38 mmol) then Pd(OAc)₂ (492 mg; 2.19 mmol) were added and thereaction mixture was heated at 100° C. for 15 h. The reaction was cooleddown to rt, poured into H₂O and EtOAc was added. The mixture wasfiltered through a pad of Celite® and the filtrate was extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and evaporated until dryness. The residue (12 g) was purifiedby chromatography over silica gel (irregular SiOH; 15-40 μm; 120 g;gradient: from 0.1% NH₄OH, 96% DCM, 4% MeOH to 0.1% NH₄OH, 92% DCM, 8%MeOH). The pure fractions were collected and the solvent was evaporatedto give 6.2 g (62%, 50/50 by LCMS) of a mixture of intermediates 6a and6b.

Preparation of Intermediate 7:

A mixture of intermediates 6a and 6b (7 g; 15.43 mmol) and platinum (IV)oxide (713 mg; 3.09 mmol) in EtOH (200 mL) was hydrogenated at rt undera pressure of 1.2 bar of H₂ for 4 h. The reaction was filtered through apad of Celite®, rinsed with MeOH and the filtrate was evaporated to give6.8 g (97%) of intermediate 7. The product was used without purificationfor the next step.

Preparation of Intermediate 8:

A mixture of intermediate 7 (6.8 g; 14.86 mmol), manganese oxide (3.9 g;44.58 mmol) in DCM (150 mL) was stirred at rt for 1 h. The reactionmixture was filtered through a pad of Celite®, rinsed with MeOH and thefiltrate was evaporated to give 7 g (quant.) of intermediate 8. Theproduct was used without purification for the next step.

Preparation of Intermediate 9:

The experiment was performed twice on 3.5 g of intermediate 8:

At 10° C., HCl (4M in 1,4-dioxane) (9.6 mL; 38.41 mmol) was addeddropwise to a solution of intermediate 8 (3.5 g; 7.68 mmol) in DCM (115mL). The reaction mixture was stirred at rt for 5 h. The mixture wastaken-up with DCM and iced-water, basified with NH₄OH and extracted withDCM. The organic layer was dried over MgSO₄, filtered and evaporated todryness. The combined residues (5.46 g obtained from 2 experiments) waspurified by chromatography over silica gel (irregular SiOH; 15-40 μm;120 g; mobile phase: 0.1% NH₄OH, 90% DCM, 10% MeOH). The pure fractionswere collected and the solvent was evaporated to give 3.94 g (72%) ofintermediate 9.

Example A3

Preparation of Intermediate 10a and Intermediate 10b

Tributyl(1-ethoxy vinyl)tin (67.68 g; 187.40 mmol) was added to asolution of a mixture of intermediates 3a and 3b (60 g; 85.18 mmol) inanhydrous 1,4-dioxane (1.2 L) under N₂. Dichlorobis(triphenylphosphine)palladium (II) (3.59 g; 5.11 mmol) was added and the mixture was purgedagain with N₂. The reaction mixture was heated at 100° C. overnight.After cooling down to rt, a 3M aqueous solution of HCl was added and themixture was stirred at rt for 40 min. The mixture was slowly basifiedwith a saturated aqueous solution of NaHCO₃ and EtOAc was added. Themixture was extracted with EtOAc and the organic layer was washed withbrine, dried with Na₂SO₄ and evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: from DCM/EtOAc 10/1 toDCM/EtOAc 8/1). The pure fractions were collected and the solvent wasevaporated to give a 10 g of mixture of intermediate 10a andintermediate 10b and 30.5 g (54%) of intermediate 10a. The 10 g mixtureof intermediate 10a and intermediate 10b was further purified bychromatography over silica gel (eluent: from DCM/EtOAc 10/1 to DCM/EtOAc4/1). The pure fractions were collected and the solvent was evaporatedto give 1.6 g (3%) of intermediate 10b and 7 g of mixture (intermediate10a and intermediate 10b) (ratio 1/1 by NMR).

Alternative Preparation:

To a solution of a mixture of intermediates 3a and 3b (75/25 evaluatedby LC/MS) (195 g, 554 mmol) in DMSO (2000 mL) was added vinylbutylether(166 g, 1661. mmol) and TEA (400 mL, 2768 mmol, 0.7 g/mL) under N₂atmosphere. Pd(OAc)₂ (12.4 g, 55 mmol) and DPPP (45.6 g, 111 mmol) wereadded. The mixture was purged again with N₂ and heated to 100° C.overnight. After cooling down to room temperature, HCl (3M, 1845 mL,5536 mmol) was added portionwise under ice batch and the mixture wasstirred for 1 hour. The pH of the mixture was adjusted to 8 with NaHCO₃.The mixture was filtered. The cake was washed with ethyl acetate (1000mL), then dissolved in CH₂Cl₂ (1500 mL*2) and filtered. The filtrate waswashed with brine (500 mL), evaporated to give a crude yellow solid (200g) mainly containing intermediate 10a. This residue was purified bysilica gel chromatography (eluent: ethyl acetate=100%). The desiredfractions were collected and the solvent was concentrated to drynessunder vacuum to give 100 g (57%) of intermediate 10a as yellow solid.

Alternatively, the previous reaction was also carried out using EtOH assolvent at a temperature of 70° C.

Preparation of Intermediate 11:

Intermediate 11 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 4, using intermediate 10a asstarting material. The aqueous layer was extracted with DCM (2×). Theorganic layers were separated, washed with water, dried over MgSO₄,filtered and evaporated to dryness. The crude product was taken-up withdiethylether, the precipitate was filtered off and dried under vacuum togive 3 g (63%, yellow solid) of intermediate 11. The product was usedwithout purification for the next step.

Alternative Pathway:

A 1M aqueous solution of NaOH (89 mL; 89.0 mmol) was added to a solutionof intermediate 10a (9.35 g; 29.7 mmol) in THF (140 mL) and MeOH (140mL). The reaction mixture was stirred at rt for 1 h then evaporateduntil dryness under vacuum. The solid obtained was slowly acidified with1N aqueous solution of HCl and filtered. The cake was dried under vacuumthen taken-up in EtOH and evaporated under vacuum to give 8.90 g(quant., yellow solid) of intermediate 11. The product was used withoutpurification for the next step.

Preparation of Intermediate 12:

Intermediate 12 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 11 asstarting material. The reaction mixture was stirred at rt for 1 h thenevaporated under vacuum. The residue was taken-up in EtOAc and a mixtureof a saturated aqueous solution of NaHCO₃ and water (50/50) was added.The aqueous layer was separated and extracted with EtOAc (3×). Thecombined organic layers were washed with a saturated aqueous solution ofbrine (3×), dried over MgSO₄, filtered off and evaporated in vacuum. Theresidue (14.2 g, orange foam) was purified by chromatography over silicagel (Irregular SiOH; 15-40 μm; 300 g; mobile phase: 30% heptane, 70%EtOAc/MeOH (9/1)). The pure fractions were collected and the solvent wasevaporated to give 7.80 g (80%, yellow solid) of intermediate 12.

Example A4

Preparation of Intermediate 13a and Intermediate 13b

Intermediate 12 (1.30 g; 3.96 mmol) was added to a solution of(R)-(+)-2-methyl-2-propanesulfmamide (1.44 g; 11.9 mmol) andtitanium(IV) ethoxide (4.98 mL; 23.8 mmol) in THF (42 mL) at rt. Thereaction mixture was heated at reflux (70° C.) for 18 h. Then, thereaction mixture was cooled down to −50° C. and NaBH₄ (150 mg; 3.96mmol) was added portion wise. The mixture was allowed to slowly warm tort and stirred for 1 h. The mixture was cooled down to 0° C. and MeOHwas slowly added (bubbling in the mixture). The crude was then pouredinto a saturated aqueous solution of NaCl and filtered. The cake wasrinsed with EtOAc and the filtrate was extracted with EtOAc. The organiclayer was separated, washed with water, dried over MgSO₄, filtered offand evaporated under vacuum. The residue (2.30 g) was purified bychromatography over silica gel (Irregular SiOH; 15-40 μm; 80 g; mobilephase: 70% heptane, 30% iPrOH/NH₄OH (9/1)). The pure fractions werecollected and the solvent was evaporated. The residue (800 mg) wascombined with another little batch (34 mg) and the mixture was purifiedby chromatography over silica gel (Irregular SiOH; 15-40 μm; 30 g;gradient: from 100% DCM to 90% DCM, 10% iPrOH). The pure fractions werecollected and the solvent was evaporated to give 260 mg (15%) ofintermediate 13a and 175 mg (10%) of intermediate 13b (first producteluted by chromatography).

Preparation of Intermediate 14:

HCl (4M in 1,4-dioxane) (192 μL; 767 μmol) was added to a solution ofintermediate 13a (334 mg; 767 μmol) in 1,4-dioxane (7.6 mL). Thereaction mixture was stirred at rt for 1 h. The mixture was combinedwith another batch coming from a reaction performed on 20 mg ofintermediate 13a and basified with a saturated aqueous solution ofNaHCO₃. The aqueous layer was separated and extracted with EtOAc (3×).The combined organic layers were dried over MgSO₄, filtered andevaporated under vacuum. The residue (265 mg) was purified bychromatography over silica gel (Irregular SiOH; 15-40 μm; 10 g;gradient: from 100% DCM to 90% DCM, 10% (9/1) MeOH/NH₄OH). The purefractions were collected and the solvent was evaporated to give 95 mg(37%, yellow foam) of fraction 1 and 53 mg (21%, yellow foam) offraction 2. Fraction 2 was purified by achiral SFC (CHIRALPAK AD-H; 5 μm250×20 mm; mobile phase: 75% CO₂, 25% MeOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 37 mg(15%, yellow film) of intermediate 14.

Fraction 1 was purified by chromatography over silica gel (IrregularSiOH; 15-40 μm; 10 g; gradient: from 100% DCM to 90% DCM, 10% (9/1)MeOH/NH₄OH). The pure fractions were collected and the solvent wasevaporated. The residue (yellow foam) was purified by chiral SFC(CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 75% CO₂, 25% MeOH (0.3%iPrNH₂)). The pure fractions were collected and the solvent wasevaporated to give 59 mg (23%, pale yellow film) of intermediate 14.

Example A5

Preparation of Intermediate 15:

Cerium(III) chloride (8.2 g; 33.3 mmol) was added to a solution ofintermediate 10a (10 g; 31.7 mmol) in MeOH (220 mL) and DCM (100 mL).The reaction mixture was stirred at rt for 30 min. The mixture wascooled down to 0° C. and NaBH₄ (1.32 g; 34.9 mmol) was added portionwise(bubbling in the mixture). The reaction mixture was stirred at rt for 1h 30. Then, DCM and water were added. The layers were separated, theaqueous layer was extracted with DCM (2×) and the combined organicslayers were dried over MgSO₄, filtered off and evaporated in vacuum. Theresidue (9.65 g) was recrystallized with MeOH and diethylether. Theprecipitate was filtered and dried to give 7.98 g (79%) of intermediate15.

Alternative Pathway:

NaBH₄ (1.01 g; 26.6 mmol) was added to a solution of intermediate 10a(7.94 g; 22.2 mmol) in MeOH (140 mL) and DCM (70 mL) at 0° C. Thereaction mixture was slowly warmed to rt and stirred for 30 min. Themixture was slowly quenched with water. DCM was added and the layerswere separated. The aqueous layer was extracted with DCM (2×). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedunder vacuum. The residue (7.9 g, orange solid) was purified bychromatography over silica gel (regular SiOH; 30 μm; 300 g; gradient:from 70% DCM, 30% EtOAc to 30% DCM, 70% EtOAc). The pure fractions werecollected and the solvent was evaporated. The residue (5.35 g, yellowsolid) was triturated in diethylether and filtered to give 4.95 g (70%,pale yellow solid) of intermediate 15.

Preparation of Intermediate 15a and Intermediate 15b

Intermediate 15a and intermediate 15b were obtained after chiral SFC(Stationary phase: CHIRALPAK IC 5 μm 250×30 mm, Mobile phase: 55% CO₂,45% EtOH (0.3% iPrNH₂)) of intermediate 15. Crystallization from ACN anddiethylether afforded 444 mg (22%) of intermediate 15a (M.P.: 163° C.,DSC) and 593 mg (30%) of intermediate 15b (M.P.: 146° C., DSC).

Alternative Preparation of Intermediate 15b

Intermediate 10a and (−)-B-chlorodiisopinocampheylborane (1.25 eq.) werestirred in dichloromethane (10 volumes) at −35° C. After completeconversion, diethanolamine (2.7 eq.) was added to remove the boronbyproducts. The mixture was refluxed for two hours and the solid formedwas filtered and discarded. The filtrate was washed twice with water,concentrated to 1-2 volumes and petrol ether was added. The solid wasfiltered and re-slurried in methyl tertiobutylether. The procedure wasexecuted on 50 g, 200 g and 300 g scale of intermediate 10a in 93%average yield (e.e.: 90%).

Preparation of Intermediate 16:

Intermediate 16 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 4, using intermediate 15 asstarting material. At 0° C., the solution was acidified with 3N aqueoussolution of HCl slowly and stirred at 10° C. for 1 h. The precipitatewas filtered and dried to give 1.4 g (39%) of intermediate 16. Thefiltrate was extracted with DCM (2×). The organic layers were combined,washed with water, dried over MgSO₄, filtered and evaporated to giveadditional 1.8 g (50%, yellow solid) of intermediate 16. The 2 batcheswere combined to give 3.2 g (89% global yield) of intermediate 16directly use in the next step without any further purification.

Alternative Pathway:

Intermediate 16 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 11 (alternativepreparation), using intermediate 15 as starting material. The reactionmixture was stirred at rt overnight then evaporated until dryness undervacuum. The solid obtained was slowly acidified with a 1N aqueoussolution of HCl and filtered on a glass frit to give 1.4 g (100%,off-white solid) of intermediate 16.

Preparation of Intermediate 17:

Intermediate 17 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 16 asstarting material. The residue was taken-up in EtOAc and a mixture of asaturated aqueous solution of NaHCO₃ was added. The aqueous layer wasseparated and extracted with EtOAc (2×) and DCM/MeOH (9/1) (2×). Thecombined organic layers were dried over MgSO₄, filtered off andevaporated under vacuum. The residue (2.1 g, orange oil) was purified bychromatography over silica gel (regular SiOH; 30 μm; 80 g; gradient:100% DCM to 30% DCM, 70% EtOAc). The pure fractions were collected andthe solvent was evaporated to give 220 mg (14%, orange foam, not pure byNMR) of intermediate 17 and 905 mg (59%, yellow foam) of intermediate17.

Alternative Pathway:

Intermediate 17 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15 (alternative pathway),using intermediate 12 as starting material. The reaction mixture wasstirred at 0° C. for 15 min. The mixture was quenched with water andslowly warmed to rt. The aqueous layer was extracted with DCM (2×), thenDCM/MeOH (9/1) (2×). The combined organics layers were dried over MgSO₄,filtered off and evaporated in vacuum. The residue (1.68 g, pale yellowfoam) was purified by chromatography over silica gel (irregular SiOH;15-40 μm; 50 g; eluent: from 100% DCM to 96% DCM, 4% MeOH). The purefractions were collected and the solvent was evaporated to give 1.29 g(79%, pale yellow foam) of intermediate 17.

Alternative Pathway:

Intermediate 17 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 12 asstarting material. The reaction mixture was stirred at rt for 15 h.Then, DCM and ice-water were added and the mixture was stirred at rt for1 h. The aqueous layer was extracted with DCM (2×) and the combinedorganics layers were dried over MgSO₄, filtered off and evaporated invacuum. The residue was taken-up with diethylether, the precipitate wasfiltered and dried to give 1.73 g (87%) of intermediate 17.

Example A6

Preparation of Intermediate 18:

Phtalimide (2.54 g; 17.3 mmol), PPh₃ (4.53 g; 17.3 mmol) anddi-tert-butyl azodicarboxylate (3.97 g, 17.3 mmol) were added to asolution of intermediate 17 (3.80 g; 11.5 mmol) in THF (110 mL). Thereaction mixture was stirred at rt for 18 h. Then, the mixture wasevaporated under vacuum and the residue (16 g, orange foam) was purifiedby chromatography over silica gel (regular SiOH; 30 μm; 300 g; gradient:from 70% heptane, 30% EtOAc/MeOH (9/1) to 30% heptane, 70% EtOAc/MeOH(9/1)). The pure fractions were collected and the solvent was evaporatedto give 4.62 g (49%, pale brown foam) of intermediate 18.

Preparation of Intermediate 19:

Hydrazine monohydrate (1.50 mL; 24.5 mmol) was added to a suspension ofintermediate 18 (2.35 g; 2.46 mmol) in EtOH (24 mL). The reactionmixture was heated at 80° C. for 18 h. Then, the mixture was cooled downto rt and filtered. The solid was rinsed with EtOH and the filtrate wasevaporated under vacuum. The residue (2.35 g, orange solid) was combinedwith another batch coming from a reaction performed on 2.27 g ofintermediate 18, and the resulting product was diluted in DCM/MeOH(9/1). The precipitate was filtered on a glass frit and the filtrate wasevaporated under vacuum and purified by chromatography over silica gel(regular SiOH; 30 μm; 200 g; gradient: from 100% DCM to 90% DCM, 10%MeOH/NH₄OH (9/1)). The pure fractions were collected and the solvent wasevaporated to give 835 mg (45%, brown oil) of intermediate 19.

Example A7

Preparation of Intermediate 20a and Intermediate 20b

A mixture of intermediate 20a and intermediate 20b was preparedaccording to an analogous procedure as described for the synthesis ofintermediate 6, using intermediate 3a as starting material. The residue(3.2 g) was purified by chromatography over silica gel (irregular SiOH;15-40 μm; 80 g; eluent: 99% DCM, 1% MeOH). The pure fractions werecollected and the solvent was evaporated to give 1.9 g (79%) of amixture of intermediate 20a and intermediate 20b.

Alternative Pathway:

In a sealed glassware, a mixture of intermediate 3a and intermediate 3b(75/25) (10 g; 28.39 mmol), N-boc-2,3-dihydro-1H-pyrrole (6.86 mL; 39.75mmol) and K₂CO₃ (11.8 g; 85.18 mmol) in 1,4-dioxane (250 mL) was bubbledwith N₂. Then, PPh₃ (1.49 g; 5.68 mmol) and Pd(OAc)₂ (640 mg; 2.84 mmol)were added. The reaction mixture was heated to 100° C. for 5 h. Thereaction mixture was cooled down to rt, poured onto water and extractedwith EtOAc. The organic layer was decanted, washed with brine, driedover MgSO₄, filtered and evaporated to dryness. The residue (21 g) waspurified by chromatography over silica gel (irregular SiOH; 20-45 μm;450 g; mobile phase: 62% heptane, 3% MeOH (+10% NH₄OH), 35% EtOAc). Thepure fractions were collected and evaporated to dryness yielding 2.3 g(17%, impure) of intermediate 20a and 8.2 g (59%) of intermediate 20a.

Intermediate 21 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 7, using intermediate 20a asstarting material. The reaction mixture was stirred at rt for 45 min.intermediate 21 (11 g, 100%) was directly used without any furtherpurification in the next step.

Preparation of Intermediate 22a, Intermediate 22b and Intermediate 22c

Intermediate 22a were prepared according to an analogous procedure asdescribed for the synthesis of intermediate 8, using intermediate 21 asstarting material. The residue (12 g) was purified by chromatographyover silica gel (irregular SiOH; 15-40 μm; 800 g; mobile phase: 99% DCM,1% MeOH). The pure fractions were collected and the solvent wasevaporated to give respectively 3.7 g (31%) of intermediate 22a andadditional 7.3 g (61%) of intermediate 22a. This last fraction waspurified by chiral SFC (Whelk 01 (S,S) 5 μm; 250*21.1 mm; mobile phase:60% CO₂, 40% EtOH). The pure fractions were collected and the solventwas evaporated to give 3.45 g (29%) of intermediate 22b and 3.38 g (28%)of intermediate 22c.

Preparation of Intermediate 23:

Intermediate 23 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 9, using intermediate 22a asstarting material. The reaction mixture was stirred at rt for 15 h. Themixture was poured into DCM and a saturated aqueous solution of NaHCO₃then, extracted with DCM (3×). The organic layer was separated, driedover MgSO₄, filtered and evaporated to dryness. The residue was taken-upwith Et₂O. The precipitate was filtered and dried to give 3.5 g (90%) ofintermediate 23.

Preparation of Intermediate 24:

Intermediate 24 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 22bas starting material. 8.4 g (88%) of intermediate 24 was obtained.

Preparation of Intermediate 25:

Intermediate 25 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 22cas starting material. 2 1.68 g (75%) of intermediate 25 was obtained.

Example A8

Preparation of Intermediate 26a and Intermediate 26b

In a Schlenk tube, a mixture of intermediate 2a (4.0 g; 13.27 mmol),3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (3.34 g; 15.92 mmol),K₃PO₄ (8.45 g; 39.80 mmol) in 1,4-dioxane (80 mL) and H₂O (8 mL) wascarefully degassed under vacuum and back-filled with N2 (3×). Then,Pd.Cl₂(dppf).DCM (0.54 g; 0.66 mmol) was added. The mixture wascarefully degassed under vacuum and back-filled with N₂ (3×) and thenstirred at 80° C. for 8 h. After cooling down to rt, the mixture wasdiluted with DCM and filtered through a pad of Celite®. The filtrate wasevaporated under vacuum. The residue (brown) was purified bychromatography over silica gel (Regular SiOH; 30 μm; 200 g; eluent: from100% DCM to 85% DCM, 15% EtOAc). The pure fractions were collected andthe solvent was concentrated until precipitation. The solid was filteredand dried to give 2.7 g (58%, beige solid) of a mixture of intermediate26a and 26b (92/8 evaluated by 1H NMR). The filtrate was evaporatedunder vacuum to give additional 455 mg (10%, pale brown solid) of amixture of intermediate 26a and 26b (80/20 evaluated by ¹H NMR)

Preparation of Intermediate 27a and Intermediate 27b

In a round bottom flask, at 0° C., to a mixture of intermediate 26a and26b (2.7 g; 7.35 mmol; 92/8) in EtOH (50 mL) and THF (50 mL) was added1M aqueous NaOH (14.7 mL, 14.7 mmol). The reaction mixture was stirredallowing the temperature to reach rt over 1 h. Additional THF (20 mL)and EtOH (20 mL) were added and the stirring was continue for 1 hour.Then, the solvent were evaporated. The resulting residue was dilutedwith water and acidified with 1M aqueous solution of HCl to pH 2. Theaqueous layer was extracted with a mixture of DCM/MeOH (9/1, 7×). Thecombined organic layers were washed with a saturated aqueous solution ofNH₄Cl, dried over MgSO₄, filtered and the solvent was evaporated to give2.27 g (92%, beige solid) of a mixture of intermediate 27a and 27b (93/7evaluated by ¹H NMR).

Preparation of Intermediate 28a and Intermediate 28b

A mixture of intermediate 28a and 28b was prepared according to ananalogous procedure as described for the synthesis of intermediate 5,using a mixture of intermediate 27a and 27b as starting material. Thereaction mixture was stirred at rt for 18 h. The residue (6.6 g) wasmixed with crude coming from a reaction performed on 380 mg of a mixtureof intermediate 27a and 27b (˜85/15, evaluated by ¹H NMR) and theresulting residue was purified by chromatography over silica gel(regular SiOH; 30 μm; 200 g; mobile phase: from 100% DCM to 98% DCM, 2%MeOH). The pure fractions were collected and the solvent was evaporated.The residue (4.03 g, sticky yellow solid) was dried under vacuum for 16h to give 3.40 g (yellow sticky solid) which was triturated in Et₂O (˜10mL). The supernatant was removed and the solid was triturated once morewith Et₂O (˜10 mL). The supernatant was removed and the solid was driedto give 3.24 g (yellow solid, impure) of a mixture of intermediate 28aand 28b (92/8 evaluated by ¹H NMR). The product was used without furtherpurification for the next step.

Example A9

Preparation of Intermediate 29:

Intermediate 29 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 10, using intermediate 28 asstarting material. The reaction mixture was stirred at 80° C. for 8 h.The residue was purified by chromatography over silica gel (regularSiOH; 30 μm; 200 g; gradient: from 99% DCM, 1% iPrOH to 95% DCM, 5%iPrOH). The pure fractions were collected and the solvent was evaporatedto give 969 mg (40%, clear orange solid) of intermediate 29.

Preparation of Intermediate 30:

Intermediate 30 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 29 asstarting material. The reaction mixture was stirred at rt for 15 h. Theresidue was purified by chromatography over silica gel (irregular 15-40μm; 24 g; mobile phase: from 50% heptane, 5% MeOH, 35% EtOAc). The purefractions were collected and the solvent was evaporated to give 600 mg(73%) of intermediate 30.

Example A10

Preparation of Intermediate 31:

(R)-2-methylmorpholine hydrochloride (1.53 g; 11.11 mmol) andtriethylamine (3.09 mL; 22.22 mmol) were added to a solution ofintermediates 2a and 2b (67/23) (5 g; 11.11 mmol) in THF (100 mL). Thereaction mixture was stirred at rt for 2 h. The precipitate was filteredoff and the cake was washed with EtOAc. The filtrate was evaporatedunder vacuum and the residue (6.52 g, brown oil) was purified bychromatography over silica gel (irregular SiOH 15-40 μm; 200 g; mobilephase: from 100% DCM to 70% DCM, 30% EtOAc). The pure fractions werecollected and the solvent was evaporated to give 2.61 g (59%, yellowsolid) of intermediate 31.

Preparation of Intermediate 32:

Intermediate 32 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 4, using intermediate 31 asstarting material (2.06 g, 90%, yellow solid).

Preparation of Intermediate 33:

Intermediate 33 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 32 asstarting material (1.97 g, quant., orange foam).

Preparation of Intermediate 34a and Intermediate 34b

A mixture of intermediates 34a and 34b was prepared according to ananalogous procedure as described for the synthesis of intermediate 6,using intermediate 33 and N-boc-2,3-dihydro-1H-pyrrole as startingmaterial (1.88 g, 82%, yellow foam).

Preparation of Intermediate 35:

Intermediate 35 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 7, using a mixture ofintermediate 34a and 34b as starting material (1.76 g, 93%, green foam).

Preparation of Intermediate 36:

Intermediate 36 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 8, using intermediate 35 asstarting material (1.79 g, 100%, yellow foam).

Preparation of Intermediate 37:

HCl (4M in 1,4-dioxane) (4.67 mL; 18.68 mmol) was added to a solution ofintermediate 36 (1.79 g; 3.74 mmol) in 1,4-dioxane (37 mL). The reactionmixture was stirred at 50° C. overnight. The mixture was cooled to rtand evaporated under vacuum. The residue was taken-up in DCM and water.The aqueous layer was slowly basified with NaHCO₃ (solid). The layerswere separated and the aqueous layer was extracted with DCM (2×) andwith DCM/MeOH (9/1) (2×). The combined organic layer were dried overMgSO₄, filtered and evaporated under vacuum. The residue (1.32 g, orangefoam) was purified by chromatography over silica gel (irregular SiOH15-40 μm; 50 g; gradient: from 100% DCM to 90% DCM, 10% MeOH (+5%NH₄OH)). The pure fractions were collected and the solvent wasevaporated to give 1.08 g (77%, yellow foam) of intermediate 37.

Example A11

Preparation of Intermediate 40:

Intermediate 40 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 andmorpholine as starting material (1.61 g, 84%).

Preparation of Intermediate 41:

Intermediate 41 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 10, using intermediate 40 asstarting material (1.28 g, 87%).

Alternative Pathway:

Intermediate 41 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 11 andmorpholine as starting material (2.6 g, 85%).

Preparation of Intermediate 42:

Intermediate 42 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 41 asstarting material (1 g, 83%).

Alternative Pathway:

Intermediate 42 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 16 andmorpholine as starting material (3 g, 76%).

Example A12

Preparation of Intermediate 43:

Intermediate 43 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 18, using intermediate 42and phtalimide as starting material (386 mg, 79%).

Preparation of Intermediate 44:

Intermediate 44 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 19, using intermediate 43and hydrazine monohydrate as starting material (152 mg, 53%).

Example A13

Preparation of Intermediate 45:

In a sealed tube, at 10° C., phosphorus tribromide (0.67 mL; 7.05 mmol)was added dropwise to a solution of intermediate 42 (1.75 g; 4.70 mmol)in DCM (20 mL). The reaction mixture was stirred at rt for 72 h. Aprecipitate was filtered, washed with Et₂O and dried to give 1.5 g (62%)of intermediate 45.

Preparation of Intermediate 87:

Intermediate 87 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 45, using intermediate 15 asstarting material (3.3 g, 57%).

Example A14

Preparation of Intermediate 49:

Under N₂, N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (108μL; 0.59 mmol) was added to a solution of compound 251 (130 mg; 0.30mmol), HBTU (224 mg; 0.59 mmol) and DIPEA (305 μL; 1.77 mmol) in DMF (4mL) at rt. The solution was stirred at rt for 72 h. The solution waspoured into ice-water. The product was extracted with EtOAc and washedwith brine. The organic layer was dried over MgSO₄, filtered andevaporated to dryness. The residue (190 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 24 g; mobile phase:95% DCM, 5% MeOH, 0.1% NH₄OH). The pure fractions were collected and thesolvent was evaporated to give 150 mg (85%) of intermediate 49.

Preparation of Intermediate 50:

Intermediate 50 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using compound 251 andN-methyl-N-[2-(methylamino)ethyl]-1,1-dimethylethyl ester carbamic acidas starting material (450 mg, >100%).

Preparation of Intermediate 85:

Intermediate 85 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using compound 62 andN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester as startingmaterials (193 mg, 71%).

Preparation of Intermediate 187:

Intermediate 187 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49 using compound 263 asstarting materials (1.17 g, used without purification for the nextstep).

Preparation of Intermediate 188:

Intermediate 188 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using compound 170 and(S)-tert-Butyl 3-(methylamino) pyrrolidine-1-carboxylate as startingmaterials (1.02 g; 44% of purity evaluated by LC/MS).

Preparation of Intermediate 189:

Intermediate 189 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49 using compound 170 and(S)-3-(N-Boc-N-methylamino) pyrrolidin as starting materials (760 mg,used without purification).

Example A15

Preparation of Intermediate 51:

Sodium hydride (71 mg; 1.77 mmol) was added to a solution oftrimethylsulfonium iodide (361 mg; 1.77 mmol) in THF (10 mL) at rt underN₂ flow. After 1 h at 50° C., a solution of compound 250 (500 mg; 1.18mmol) in THF (10 mL) was added dropwise. The reaction mixture was heatedat 70° C. for 1 h. The mixture was poured into water and the product wasextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. The residue (650 mg) was purifiedby chromatography over silica gel (50 g; mobile phase: 98% DCM, 2% MeOH,0.1% NH₄OH). The pure fractions were collected and the solvent wasevaporated to give 450 mg (87%) of intermediate 51.

Example A16

Preparation of Intermediate 52:

At 10° C., thionyl chloride (0.39 mL; 5.37 mmol) was added to a solutionof intermediate 42 (1 g; 2.69 mmol) in DCM (20 mL) under N₂. Thesolution was stirred at 10° C. for 4 h. The mixture was evaporated togive 1.05 g (100%) of intermediate 52. The crude intermediate wasdirectly used without purification in the next step.

Preparation of Intermediate 105:

Intermediate 105 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 52, using intermediate 15 asstarting material (15 g).

Preparation of Intermediate 119:

Intermediate 119 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 52, using intermediate 17 asstarting material (1 g, >100%). The crude product was used withoutpurification in the next step.

Preparation of Intermediate 139:

Intermediate 139 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 52, using intermediate 138as starting material (370 mg, quant.). The product was used withoutpurification in the next step.

Preparation of Intermediate 145:

Intermediate 145 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 52, using intermediate 56 asstarting material (9 g, quant.). The product was used withoutpurification for the next step.

Example A17

Preparation of Intermediate 53a: And Intermediate 53b

A mixture of intermediate 53a and intermediate 53b was preparedaccording to an analogous procedure as described for the synthesis ofintermediate 1a, using 3,5-dibromo-1,2-benzenediamine and2,2-dihydroxy-acetic acid as starting material (59 g, 90%).

Preparation of Intermediate 54a and Intermediate 54b

A mixture of intermediate 54a and intermediate 54b was preparedaccording to an analogous procedure as described for the synthesis ofintermediate 3a, using a mixture of intermediates 54a and 54b andmorpholine as starting material (41.5 g, 92%).

Preparation of Intermediate 55a and Intermediate 55b

The experiment was performed twice on the same quantity (15 g; 40.2mmol) of a mixture of intermediates 54a and 54b:

In a Schlenck reactor, a solution of mixture of intermediates 54a and54b (15 g; 40.2 mmol) and tributyl(l-ethoxyvinyl)tin (14.9 mL; 44.2mmol) in 1,4-dioxane (400 mL) was degassed under N₂. Pd(PPh₃)₄ (2.32 g;2.01 mmol) was added and the mixture was degassed under N₂ and washeated at 100° C. overnight. Then, more Pd(PPh₃)₄ (2.32 g; 2.01 mmol)was added. The reaction mixture was degassed under N₂ and heated at 100°C. for 24 h. The mixture was quenched with a 1M aqueous solution of HCl(120 mL) and stirred at rt for 30 min. The resulting solution wasbasified with NaHCO₃ solid. The 2 batches were combined and filteredthrough a pad of Celite®. The cake was washed with water and EtOAc. Theaqueous layer was extracted with EtOAc. The combined organic layers weredried over MgSO₄, filtered and evaporated under vacuum. The crudeproduct was triturated in Et₂O and filtered. The precipitate (23 g,yellow solid) was purified by chromatography over silica gel (irregularSiOH; 15-40 μm; 330+220 g; gradient: 63% heptane, 35% EtOAc, 2% MeOH).The fractions containing the product were collected and the solvent wasevaporated. The residue (15 g, pale yellow solid) was further purifiedby chromatography over silica gel (Irregular SiOH 20-45 μm; 450 g;mobile phase: 99.5% DCM, 0.5% MeOH) and then by achiral SFC (CHIRALPAKIC 5 μm 250×30 mm; mobile phase: 45% CO₂, 55% MeOH (0.3% iPrNH₂) (7.3%DCM)). The pure fractions were collected and the solvent was evaporatedto give 2.7 g (9%, pale yellow solid) of intermediate 54a, 3.0 g (11%,yellow solid) of intermediate 55a and 1.06 g (3%, yellow solid) ofintermediate 55b.

Preparation of Intermediate 56:

Intermediate 56 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 55aas starting material (200 mg, 99%).

Alternative Pathway:

Intermediate 56 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15 (alternative pathway),using intermediate 55a as starting material (396 mg, 54%).

Preparation of Intermediate 58:

A solution of compound 277 (282 mg; 0.63 mmol),1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole(226 mg; 0.81 mmol) and K₂CO₃ (173 mg; 1.25 mmol) in 1,4-dioxane (4.27mL) and water (0.64 mL) was degassed under N₂. Pd.Cl₂(dppf).DCM (51 mg;62.6 μmol) was added and the reaction mixture was heated at 95° C.overnight. The resulting suspension was quenched with water (10 mL) andextracted with EtOAc (3×20 mL). The combined organic layers were driedover MgSO₄, filtered and evaporated under reduced pressure. The residuewas purified by chromatography over silica gel (irregular SiOH; 15-40μm; 12 g; gradient: from 100% heptane to 90% EtOAc, 10% MeOH (+5%NH₄OH)). The pure fractions were collected and the solvent wasevaporated to give 127 mg (39%, brown solid) of intermediate 58.

Example A18

Preparation of Intermediate 59:

Intermediate 59 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 1a, using intermediate5-bromo-3,4-pyridinediamine and ethyl glyoxalate solution (50% intoluene) as starting materials (53.5 g, 47%).

Preparation of Intermediate 60:

Intermediate 60 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 3a, using intermediate 59and morpholine as starting materials (30 g, 44%).

Preparation of Intermediate 61a and Intermediate 61b

A mixture of intermediate 61a and 61b was prepared according to ananalogous procedure as described for the synthesis of intermediate 6aand intermediate 6b, using intermediate 60 andN-boc-2,3-dihydro-1H-pyrrole as starting materials (800 mg, 62%).

Preparation of Intermediate 62a and Intermediate 62b

A mixture of intermediates 62a and 62b was prepared according to ananalogous procedure as described for the synthesis of intermediate 7,using a mixture of intermediates 61a and 61b and platinum (IV) oxide asstarting materials at atmospheric pressure for 3 h (750 mg, quant.).

Preparation of Intermediate 63:

Intermediate 63 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 8, using a mixture ofintermediates 62a and 62b and manganese oxide as starting materials (623mg, 83%).

Preparation of Intermediate 64:

Intermediate 64 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 9, using intermediate 63 asstarting material (300 mg, 65%).

Example A19

Preparation of Intermediate 65:

Intermediate 65 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 3a, using intermediate 2aand 2-methylmorpholine as starting materials (1.58 g, 81%, yellowsolid).

Preparation of Intermediate 66:

Intermediate 36 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 4, using intermediate 65 asstarting material (1.39 g, 92%, yellow solid).

Preparation of Intermediate 67:

Intermediate 67 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 66 asstarting material (1.43 g, 96%, yellow foam).

Preparation of Intermediate 68a and Intermediate 68b

A mixture of intermediates 68a and 68b was prepared according to ananalogous procedure as described for the synthesis of intermediate 6,using intermediate 67 and N-boc-2,3-dihydro-1H-pyrrole as startingmaterials (370 mg, 81%, yellow oil).

Preparation of Intermediate 69:

A mixture of intermediates 68a and 68b (370 mg; 0.79 mmol) and platinum(IV) oxide (37 mg; 0.16 mmol) in MeOH (4 mL) and THF (4 mL) washydrogenated at rt under pressure of 1 bar of Eh for 16 h. Then, moreplatinum (IV) oxide (18 mg; 0.08 mmol) was added and the mixture washydrogenated at rt under pressure of 1 bar of H₂ for 16 h. The reactionwas filtered through a pad of Celite® and rinsed with MeOH. The filtratewas combined with another batch from 30 mg of intermediates 68a and 68band was evaporated to give 355 mg (82%) of intermediate 69. The productwas directly used in the next step without any further purification.

Preparation of Intermediate 70:

Intermediate 70 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 8, using intermediate 69 asstarting material (279 mg, 79%, yellow foam).

Alternative Pathway:

Sec-Butyllithium (1.3M in THF) (2.29 mL; 2.97 mmol) was added to asolution of N-Boc-pyrrolidine (521 μL; 2.97 mmol) andN,N,N′,N′-tetramethylenediamine (446 μL; 2.97 mmol) in THF (3.72 mL)under N₂ at −78° C. The solution was stirred 1 h 30 at −78° C. Zincchloride (2M in Me-THF) (1.49 mL; 2.97 mmol) was added slowly. Thereaction was stirred 30 min at −78° C. then 1 h at rt. Intermediate 67(600 mg; 1.49 mmol), Pd(OAc)₂ (13 mg; 0.06 mmol) andtri-tert-butylphosphonium tetrafluoroborate (35 mg; 0.12 mmol) wereadded. Then, the reaction mixture was heated at 60° C. for 30 min. Themixture was combined with another batch coming from a reaction performedon 500 mg of intermediate 67. The mixture was quenched with a saturatedsolution of NH₄Cl and extracted with EtOAc. The organic layer was driedover MgSO₄, filtered and evaporated in vacuum. The residue (2.2 g,orange oil) was purified by chromatography over silica gel (regular SiOH30 μm; 80 g; gradient: from 80% DCM, 20% EtOAc to 100% EtOAc). The purefractions were collected and the solvent was evaporated to give 156 mg(12%, yellow foam) of intermediate 70.

Preparation of Intermediate 71:

Intermediate 71 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 37, using intermediate 70 asstarting material (157 mg, 69%, orange oil).

Example A20

Preparation of Intermediate 74:

Intermediate 74 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 32 and(R)-2-methylmorpholine as starting materials (2.76 g, quant.). Theproduct was directly used without any purification in the next step.

Preparation of Intermediate 75:

Intermediate 75 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 10a, using intermediate 74as starting material (316 mg, 74%).

Preparation of Intermediate 76:

Intermediate 76 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 75 asstarting material (81 mg, 67%).

Example A21

Preparation of Intermediate 77:

Intermediate 77 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 and1-methylpiperazine as starting materials (1.6 g, 86%).

Preparation of Intermediate 78a and Intermediate 78b

A mixture of intermediate 78a and 78b was prepared according to ananalogous procedure as described for the synthesis of intermediates 6aand 6b, using intermediate 77 and N-boc-2,3-dihydro-1H-pyrrole asstarting materials (1.2 g, 62%, ratio by ¹H NMR: 65/35).

Preparation of Intermediate 79:

Intermediate 79 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 7, using a mixture ofintermediates 78a and 78b in MeOH as starting materials (1.2 g, quant.).

Preparation of Intermediate 80a, Intermediate 80b and Intermediate 80c

A mixture of intermediate 79 (1.2 g; 2.34 mmol), manganese oxide (0.61g; 7.02 mmol) in DCM (30 mL) was stirred at rt for 1 h. The reactionmixture was filtered through a pad of Celite®, rinsed with MeOH and thefiltrate was evaporated. The residue (1.1 g) was purified bychromatography over silica gel (irregular 15-40 μm; 50 g; mobile phase:40% heptane, 10% MeOH (+10% NH₄OH), 50% EtOAc). The pure fractions werecollected and the solvent was evaporated to give 0.58 g (48%) ofintermediate 80a. The racemic product was purified by chiral SFC (Whelk01 (S,S) 5 μm 250*21.1 mm; mobile phase: 45% CO₂, 55% MeOH). The purefractions were collected and the solvent was evaporated to give 265 mg(22%) of intermediate 80b and 265 mg (22%) of intermediate 80c.

Preparation of Intermediate 81:

Intermediate 81 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 9, using intermediate 80b asstarting material (100 mg, 47%).

Preparation of Intermediate 82

Intermediate 82 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 9, using intermediate 80c asstarting material (120 mg, 56%).

Example A22

Preparation Intermediate 86:

In a sealed tube, a mixture of compound 78 (290 mg; 0.57 mmol),N-boc-1,2-diaminoethane (179 μL; 1.13 mmol) and Cs₂CO₃ (554 mg; 1.70mmol) in 2-methyl-2-butanol (2.76 mL) was carefully degassed undervacuum and back-filled with N₂. BrettPhos Precatalyst First Gen (23 mg;0.03 mmol) and BrettPhos (6 mg; 0.01 mmol) were added. The reactionmixture was carefully degassed under vacuum and back-filled with N₂ andheated at 110° C. for 3 h. After cooling down to rt, BrettPhosPrecatalyst First Gen (23 mg; 0.03 mmol) and BrettPhos (6 mg; 0.01 mmol)were added. The reaction mixture was degassed in vacuum and back-filledwith N₂ and heated at 110° C. for 4 h. After cooling down to rt, themixture was combined with a batch coming from a reaction performed on 40mg of compound 78. The crude was diluted with EtOAc and filtered througha pad of Celite®. The filtrate was evaporated in vacuum to dryness. Theresidue (758 mg, brown oil) was purified by chromatography over silicagel (Irregular SiOH 15-40 μm; 40 g; gradient: from 85% heptane, 13.5%EtOAc, 1.5% MeOH to 50% heptane, 45% EtOAc, 5% MeOH). The pure fractionswere collected and the solvent was evaporated. The residue (309 mg) waspurified by chromatography over silica gel (Irregular bare silica; 40 g;mobile phase: 53% heptane, 7% MeOH (+10% NH₄OH), 35% EtOAc). The purefractions were collected and the solvent was evaporated to give 180 mg(55%, pale yellow foam) of intermediate 86.

Example A23

Preparation of Intermediate 88:

Pyridinium p-toluenesulfonate (409 mg; 1.63 mmol) and3,4-dihydro-2H-pyran (2.98 mL; 32.6 mmol) were added to a solution of(S)-2-hydroxymethylmorpholine hydrochloride (2.5 g; 16.28 mmol) in DCM(160 mL). The reaction mixture was stirred at rt overnight. Then, asaturated aqueous solution of NaHCO₃ was added and the layers wereseparated. The organic layer was dried over MgSO₄, filtered and thesolvent was evaporated under vacuum to give 2.29 g (70%, yellow oil) ofintermediate 88.

Preparation of Intermediate 89:

Intermediate 89 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 31, using intermediate 2aand intermediate 88 as starting materials (1.42 g, 92%, yellowcrystals).

Preparation of Intermediate 90:

Intermediate 90 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 11, using intermediate 89 asstarting material. The reaction mixture was stirred at rt overnight. Themixture was evaporated under vacuum and the residue was slowly acidifiedwith 10% aqueous solution of NH₄Cl. Then, DCM was added and the layerswere separated. The organic layer was washed with saturated aqueoussolution of NH₄Cl and the product was extracted with DCM/MeOH (9/1)(3×). The combined organic layer were dried over Na₂SO₄, filtered andevaporated under vacuum to give 1.5 g (yellow solid) of intermediate 90.

Preparation of Intermediate 91:

Intermediate 81 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 90 andazetidine hydrochloride as starting materials (407 mg, 55%, yellowfoam).

Preparation of Intermediate 92:

Intermediate 92 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 10a, using intermediate 91as starting material (110 mg, 33%, yellow oil).

Preparation of Intermediate 93:

Intermediate 93 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15 (alternative pathway),using intermediate 92 as starting material (116 mg, pale yellow foam).

Preparation of Intermediate 94:

Intermediate 94 was prepared according to an analogous procedure asdescribed for the synthesis of compound 247, using intermediate 93 and3,5-difluorophenol as starting materials (46 mg, 34%, colorless oil).

Example A24

Preparation of Intermediate 95:

Tert-butyl 3-aminopropylcarbamate (1.31 mL; 7.49 mmol) was added to asolution of 4-fluoro-2-hydroxybenzaldehyde (1 g; 7.14 mmol) in MeOH (70mL). The reaction mixture was stirred at rt overnight. Then, sodiumborohydride (540 mg; 14.27 mmol) was added portionwise and the reactionmixture was stirred at rt for 1 h 30. The mixture was slowly quenchedwith a saturated aqueous solution of NH₄Cl. The mixture was evaporatedunder vacuum and the residue was taken-up with EtOAc and water. Thelayers were separated. The organic layer was dried over MgSO₄, filteredand evaporated in vacuum. The residue (2.25 g, pale yellow oil) wastriturated in Et₂O and evaporated under vacuum (2×) to give 2.10 g (99%,white solid) of intermediate 95.

Preparation of Intermediate 96:

Ditert-butyl dicarbonate (878 mg; 4.02 mmol) was added to a solution ofintermediate 95 (1 g; 3.35 mmol) and triethylamine (1.40 mL; 10.06 mmol)in DCM (34 mL) at 0° C. The reaction mixture was stirred at rtovernight. Then, the mixture was washed with a saturated aqueoussolution of NaHCO₃. The organic layer was dried over MgSO₄, filtered andevaporated under vacuum. The residue (1.7 g, colourless oil) waspurified by chromatography over silica gel (irregular SiOH; 15-40 μm; 80g; eluent: from 90% heptane, 10% DCM to 10% heptane, 90% DCM). The purefractions were collected and the solvent was evaporated to give 614 mg(46%, white foam) of intermediate 96.

Preparation of Intermediate 97:

Intermediate 97 was prepared according to an analogous procedure asdescribed for the synthesis of compound 247, using intermediate 17 andintermediate 96 as starting materials (435 mg, 61%, yellow foam).

Example A25

Preparation of Intermediate 98:

A solution of 3,5-difluoroaniline (2 g; 15.49 mmol),4-nitrobenzenesulfonyl chloride (3.61 g; 16.27 mmol) and4-dimethylaminopyridine (37.9 mg; 0.31 mmol) in pyridine (60 mL) washeated at 100° C. for 18 h. After cooling down to rt, the solution wasevaporated under vacuum and taken-up in DCM. The organic layer wassuccessively washed with 1N aqueous solution of HCl (×2), water and asaturated aqueous solution of NaCl. Then, it was dried over MgSO₄,filtered and evaporated under vacuum to give 4.5 g (92%, beige solid) ofintermediate 98.

Alternative Pathway:

In a microwave tube, 4-nitrobenzenesulfonyl chloride (2.7 g; 12.20 mmol)was added to a mixture of 3,5-difluoroaniline (1.5 g; 11.62 mmol) and4-dimethylaminopyridine (28 mg; 232 μmol) in pyridine (15 mL). Themixture was heated at 100° C. using one single mode microwave with apower output ranging from 0 to 400 W for 30 min. The mixture was thenevaporated under vacuum and taken-up in DCM. The organic layer wassuccessively washed with 1N aqueous solution of HCl (×2), water and asaturated aqueous solution of NaCl. Then, it was dried over MgSO₄,filtered and evaporated under vacuum to give 2.9 g (79%, beige solid) ofintermediate 98.

Preparation of Intermediate 99:

Intermediate 99 was prepared according to an analogous procedure asdescribed for the synthesis of compound 277, using intermediate 15 andintermediate 98 as starting materials. The reaction mixture was heatedat 110° C. overnight. The mixture was cooled down to rt, poured intowater and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and evaporated to dryness. The residue waspurified by chromatography over silica gel (irregular 15-40 μm; 50 g;mobile phase: 98% DCM, 2% MeOH). The pure fractions were collected andthe solvent was evaporated. The residue (0.85 g) was purified bychromatography over silica gel (irregular 15-40 μm; 50 g; mobile phase:50% heptane, 45% EtOAc, 5% MeOH). The pure fractions were collected andthe solvent was evaporated to give 430 mg (45%) of intermediate 99.

Preparation of Intermediate 100:

Diisobutylaluminium hydride (Solution 20% in toluene) (3 mL; 3.59 mmol)was added dropwise to a solution of intermediate 99 (440 mg; 0.72 mmol)in THF (15 mL) at −70° C. under N₂. The reaction mixture was stirred for4 h at −70° C. The mixture was poured carefully into a solution of iceand NH₄Cl, then extracted with DCM. The organic layer was washed withwater and dried over MgSO₄, filtered and evaporated to dryness. Theresidue (450 mg) was purified by chromatography over silica gel(irregular 15-40 μm; 40 g; gradient: from 0.1% NH₄OH, 3% MeOH, 97% DCMto 0.1% NH₄OH, 5% MeOH, 95% DCM). The pure fractions were collected andthe solvent was evaporated to give 100 mg (24%) of intermediate 100.

Example A26

Preparation of Intermediate 103:

Compound 250 (100 mg; 0.24 mmol) was added to a solution of tert-butylmethyl[2-methylamino]ethyl]carbamate (221 mg; 1.18 mmol) and sodiumacetate (97 mg; 1.18 mmol) in MeOH (3 mL). The reaction mixture wasstirred at rt for 4 h. Then, sodium borohydride (18 mg; 0.47 mmol) wasadded portionwise at 0° C. and the reaction mixture was stirred at rtfor 1 h 30. Then, water was added and the product extracted with EtOAc.The organic layer was washed with brine (×2), then dried over MgSO₄,filtered and evaporated to give 279 mg (quant.) of intermediate 103. Thecrude product was used without purification in the next step.

Example A27

Preparation of Intermediate 104:

Diisopropyl azodicarboxylate (277 μL; 1.41 mmol) and PPh₃ (369 mg; 1.41mmol) in THF (5 mL) was stirred at rt for 15 min. A solution of compound10 (200 mg; 0.47 mmol) and phtalimide (207 mg; 1.41 mmol) in THF (5 mL)was added dropwise and the reaction mixture was heated at 40° C. for 24h. The mixture was evaporated until dryness. The residue (985 mg) waspurified by chromatography over silica gel (irregular 15-40 μm; 40 g;mobile phase: 60% heptane, 5% MeOH, 35% EtOAc). The pure fractions werecollected and evaporated to give 750 mg (quant.) of intermediate 104.

Example A28

Preparation of Intermediate 106:

Intermediate 106 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 98, using 3-fluoroanilineand 4-nitrobenzenesulfonyl chloride as starting material (4.97 g, 93%,pale brown solid).

Preparation of Intermediate 107:

Intermediate 107 was prepared according to an analogous procedure asdescribed for the synthesis of compound 277, using intermediate 15 andintermediate 106 as starting materials (2.63 g, 47%, brown solid). Thereaction mixture was heated at 120° C. for 18 h.

Preparation of Intermediate 108:

Intermediate 108 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 100, using intermediate 107as starting material (73 mg, 33%, yellow solid).

Example A29

Preparation of Intermediate 109a and Intermediate 109b

A mixture of intermediates 109a and 109b was prepared according to ananalogous procedure as described for the synthesis of intermediate 1,using 3-bromo-5-methylbenzene-1,2-diamine and 2,2-dihydroxy-acetic acidas starting materials (21 g, 100%).

Preparation of Intermediate 110a and Intermediate 110b

A mixture of intermediates 110a and 110b was prepared according to ananalogous procedure as described for the synthesis of intermediates 3aand 3b, using a mixture of intermediates 109a and 109b and morpholine asstarting materials (14.3 g, 52%, ration 1/1 by NMR).

Preparation of Intermediate 111a: And Intermediate 111b

Intermediates 111a and 111b were prepared according to an analogousprocedure as described for the synthesis of intermediate 20a(alternative pathway), using a mixture of intermediates 110a and 110band N-boc-2,3-dihydro-1H-pyrrole as starting materials (257 mg, 13% ofintermediate 111b and 833 mg, 43% of intermediate 111a).

Preparation of Intermediate 112:

Intermediate 112 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 7, using intermediate 111aas starting material (879 mg, quant.). The reaction mixture was stirredfor 1 h 30. The crude was used without purification for the next step.

Preparation of Intermediate 113:

Intermediate 113 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 8, using intermediate 112 asstarting material (782 mg, 94%). The reaction mixture was stirred at rtfor 18 h.

Preparation of Intermediate 114:

Intermediate 114 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 9, using intermediate 113 asstarting material (405 mg, 74%). The reaction mixture was stirred at rtfor 15 h.

Example A30

Preparation of Intermediate 118a and Intermediate 118b

Intermediate 118a and intermediate 118b were prepared according to ananalogous procedure as described for the synthesis of compound 5, usingcompound 257a and N-(2-aminoethyl)-N-methyl carbamic acid tert-butylester as starting materials (163 mg, 34%, pale yellow oil ofintermediate 118a and 172 mg, 32%, pale yellow oil of intermediate 118b.

Preparation of Intermediate 122:

Intermediate 122 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 98 asstarting material (324 mg, 77%).

Preparation of Intermediate 125:

Intermediate 125 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 261 andN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester as startingmaterials (450 mg, quant.).

Preparation of Intermediate 129:

Intermediate 129 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 83b andN-methyl-N-[2-(methylamino)ethyl]-1,1-dimethylethyl ester carbamic acidas starting materials (95 mg, 27%).

Example A31

Preparation of Intermediate 120:

A mixture of 3,5-difluoroaniline (15 g; 116.2 mmol), 2-bromoethanol(14.5 g; 116.2 mmol) and DIPEA (140 mL) was heated at 140° C. overnightin a sealed vessel. The reaction mixture was filtered to give 18 g (90%)of intermediate 120.

Preparation of Intermediate 121:

A mixture of intermediate 120 (10 g; 57.8 mmol), tert-butyldimethylsilylchloride (8.7 g; 57.8 mmol), imidazole (3.9 g; 57.8 mmol) in DMF (300mL) was stirred at rt overnight. The reaction was poured into water andextracted with EtOAc. The organic layer was dried over Na₂SO₄, filteredand the solvent was evaporated to give 12 g (75%) of intermediate 121.

Alternative Pathway:

In a sealed tube, a mixture of 3,5-difluoroaniline (1 g; 7.75 mmol),(2-bromoethoxy)-tertbutyldimethylsilane (1.83 mL; 8.52 mmol) and DIPEA(3.3 mL) was stirred at 140° C. overnight. The reaction mixture waspoured into water, extracted with DCM, washed with brine then with H₂O(2×). The organic layer was dried over MgSO₄, filtered and evaporateduntil dryness. The residue (3 g, brown oil) was purified bychromatography over silica gel (irregular 15-40 μm; 50 g; mobile phase:98% heptane, 2% EtOAc). The pure fractions were collected and evaporateduntil dryness to give 0.5 g (22%) of intermediate 121 and 1.5 g (notpure) which was purified by chromatography over silica gel (irregular15-40 μm; 80 g; mobile phase: 99% heptane, 1% EtOAc). The pure fractionswere collected and evaporated to give additional 650 mg (29%) ofintermediate 121.

Example A32

Preparation of Intermediate 126:

Intermediate 126 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 10, using intermediate 67and tributyl(l-ethoxyvinyl)tin as starting materials (385 mg, 69%,yellow solid).

Preparation of Intermediate 127:

Intermediate 127 (undetermined mixture of 4 diastereoisomers) wasprepared according to an analogous procedure as described for thesynthesis of intermediate 15 (alternative pathway), using intermediate126 as starting material (254 mg, 66%, yellow foam).

Example A33

Preparation of Intermediate 128:

Intermediate 128 (undetermined mixture of 4 diastereoisomers) wasprepared according to an analogous procedure as described for thesynthesis of compound 277, using intermediate 127 and intermediate 106as starting materials (126 mg, 18%, yellow solid). The reaction mixturewas stirred at 110° C. for 18 h.

Example A34

Preparation of Intermediate 132a, Intermediate 132b and Intermediate132c

Intermediate 132a were prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 263 andN-Boc-N-methylethylenediamine as starting materials. The residue (593mg, orange oil) was purified by chromatography over silica gel(Irregular SiOH 15-40 μm; 24 g; gradient: from 100% DCM to 90% DCM, 10%iPrOH/NH₄OH (95/5)). The pure fractions were collected and the solventwas evaporated. The residue (186 mg, yellow foam, intermediate 132a) waspurified by chiral SFC (CHIRALCEL OJ-H 5 μm; 250×20 mm; mobile phase:75% CO₂, 25% iPrOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give two fractions which were separatelydissolved in a minimum of DCM, precipitated with pentane then evaporatedand dried under vacuum to give respectively 89 mg (38%, yellow solid) ofintermediate 132b and 90 mg (38%, yellow solid) of intermediate 132c.

Preparation of Intermediate 135:

Intermediate 135 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 265 andN-Boc-N-methylethylenediamine as starting materials (240 mg, quant.).

Preparation of Intermediate 136:

Intermediate 136 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 83cand (N-Boc-N,N′-dimethyl)ethylenediamine as starting materials (200 mg,59%).

Preparation of Intermediate 148a, Intermediate 148b and Intermediate148c

Intermediate 148a was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 83a andintermediate 147 as starting material. Intermediate 148a (346 mg; 91%)was purified by chiral SFC (Chiralpak AS-H 5 μm; 250*20 mm; mobilephase: 80% CO₂, 20% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give 103 mg (27%) ofintermediate 148b and 100 mg (26%) of intermediate 148c.

Preparation of Intermediate 149:

Intermediate 149 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 83a andtert-butyl methyl(piperidin-4-ylmethyl)carbamate as starting materials(370 mg; quant.). The product was used without purification in the nextstep.

Preparation of Intermediate 144 and Intermediate 145

Intermediate 144 and intermediate 145 were prepared according to ananalogous procedure as described for the synthesis of intermediate 5,using compound 248 as starting materials. The racemic (737 mg) waspurified by chiral SFC (CHIRALCEL OJ-H 5 μm; 250×20 mm; mobile phase:90% CO₂, 10% EtOH). The pure fractions were collected and the solventwas evaporated to give respectively 297 mg (27%) of intermediate 144 and339 mg (31%) of intermediate 145.

Preparation of Intermediate 160:

Intermediate 160 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 270 asstarting material (500 mg; 63%).

Preparation of Intermediate 195, Intermediate 195a and Intermediate 195b

Intermediate 195 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 170 asstarting materials (520 mg; 50%). Intermediate 195 was purified bypreparative SFC (Stationary phase: Chiralpak Diacel AS 20×250 mm, Mobilephase: CO₂, iPrOH+0.4 iPrNH₂). The fractions containing the productswere collected and evaporated until dryness to give 228 mg (22%) ofintermediate 195a and 296 mg (28%) of intermediate 195b.

Preparation of Intermediate 206, Intermediate 206a and Intermediate 206b

Intermediate 206 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 234 and(S)-tert-Butyl 3-(methylamino) pyrrolidine-1-carboxylate as startingmaterials (1.1 g; 95%). The separation of the enantiomers from 1.1 g ofintermediate 206 was performed by chiral SFC (CHIRALPAK AS-H 5 μm 250×20mm; mobile phase: 70% CO₂, 30% EtOH (0.3% iPrNH₂)). The pure fractionswere collected and the solvent was evaporated to give 462 mg (40%) ofintermediate 206a and 495 mg (43%) of intermediate 206b.

Preparation of Intermediate 207, Intermediate 207a and Intermediate 207b

Intermediate 207 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 234 and(R)-1-Boc-3-Methylaminopyrrolidine as starting materials (1.05 g; 91%).The separation of the enantiomers from 1.05 g of intermediate 207 wasperformed by chiral SFC (CHIRALPAK DIACEL 250×20 mm; mobile phase: CO₂,EtOH (0.4% iPrNH₂)). The pure fractions were collected and the solventwas evaporated to give 480 mg (42%) of intermediate 207a and 504 mg(44%) of intermediate 207b.

Preparation of Intermediate 208, Intermediate 208a and Intermediate 208b

Intermediate 208 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 compound 285 andN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester as startingmaterials (1.12 g; 79%). The separation of the enantiomers from 1.12 gof intermediate 208 was performed by chiral SFC (CHIRALPAK DIACEL AD250×20 mm; mobile phase: CO₂, EtOH (0.4% iPrNH₂)). The pure fractionswere collected and the solvent was evaporated to give 518 mg (37%) ofintermediate 208a and 533 mg (38%) of intermediate 208b.

Preparation of Intermediate 209, Intermediate 209a and Intermediate 209b

Intermediate 209 prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 234 and(R)-1-boc-3-aminopyrrolidine as starting materials (960 mg; 93%). Theseparation of the enantiomers from 960 mg of intermediate 209 wasperformed by chiral SFC (CHIRALPAK AD-H 5 μm 250×30 mm; mobile phase:50% CO₂, 50% iPrOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give 407 mg (39%) of intermediate 209a and420 mg (41%) of intermediate 209b.

Preparation of Intermediate 213, Intermediate 213a and Intermediate 213b

Intermediate 213 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 234 and(S)-2-aminomethyl-1-boc-pyrrolidine as starting materials (1 g; 86%).The separation of the enantiomers from 1 g intermediate 213 wasperformed by chiral SFC (CHIRALPAK AD-H 5 μm 250×30 mm; mobile phase:60% CO₂, 40% MeOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give 416 mg (36%) of intermediate 213a and445 mg (38%) of intermediate 213b.

Preparation of Intermediate 215, Intermediate 215a and Intermediate 215b

Intermediate 215 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 170 andN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester as startingmaterials (550 mg; 99%). The separation of the enantiomers from 550 mgintermediate 215 was performed by chiral SFC (Stationary phase:Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 85% CO₂, 15% EtOH (0.3%iPrNH₂)). The pure fractions were collected and the solvent wasevaporated to give 200 mg (36%) of intermediate 215a and 237 mg (43%) ofintermediate 215b.

Preparation of Intermediate 220, Intermediate 220a and Intermediate 220b

Intermediate 220 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 285 andA-(2-aminoethyl)-A-Methyl carbamic acid tert-butyl ester as startingmaterials (1.28 g; 77%). The separation of the enantiomers from 1.28 gintermediate 220 was performed via chiral SFC (Stationary phase:CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% EtOH (0.3%iPrNH₂)). The pure fraction were collected and evaporated until drynessto give 730 mg (44%) of intermediate 220a and 716 mg (43%) ofintermediate 220b.

Preparation of Intermediate 221:

Intermediate 221 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 234 andcarbamic acid, N-methyl-N-[2-[2-(methylamino)ethoxy]ethyl]-,1,1-dimethylethyl ester as starting materials (950 mg; 78%).

Intermediate 222 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 289 andtert-butyl 1,4-diazepane-1-carboxylate as starting materials (860 mg,100%).

Preparation of Intermediate 223:

Intermediate 223 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 289 and(S)-3-(N-3-Boc-Nmethylamino)pyrolidine as starting materials (390 mg g;89%).

Preparation of Intermediate 224:

Intermediate 224 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 289 and(R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester asstarting materials (780 mg g; 100%).

Preparation of Intermediate 225, Intermediate 225a and Intermediate 225b

Intermediate 225 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5 using compound 248 andN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester as startingmaterials (220 mg).

The separation of the enantiomers was performed from 220 mg ofintermediate 225 via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm250×20 mm, Mobile phase: 80% CO2, 20% EtOH). The pure fractions werecollected and evaporated until dryness to give 43 mg (6%) ofintermediate 225a and 45 mg (6%) of intermediate 225b.

Preparation of Intermediate 226

Intermediate 226 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 307 and(R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester asstarting materials (298 mg, 100%).

Preparation of Intermediate 227

Intermediate 227 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 307 asstarting material (346 mg, 82%).

Preparation of Intermediate 228, Intermediate 228a and Intermediate 228b

Intermediate 228 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 234 and(S)-Tert-butylmethyl(pyrrolidin-3-yl)carbamate as starting materials(675 mg; 78%). The separation of the enantiomers was performed by SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 60% CO₂,40% EtOH (0.3% iPrNH₂)). The fractions containing the product were mixedand concentrated to afford 179 mg of intermediate 228a( and 190 mg ofintermediate 228b.

Preparation of Intermediate 229

Intermediate 229 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 289 and(S)-1-Boc-3-(methylamino)pyrrolidine as starting material (1.1 g, 100%).

Preparation of Intermediate 230. Intermediate 230a and Intermediate 230b

Intermediate 230 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 285 and(S)-tert-butylmethyl(pyrrolidin-3-yl)carbamate as starting materials(900 mg). The separation of the enantiomers from 900 mg of intermediate230 was performed via chiral SFC (Stationary phase: CHIRALPAK DIACEL AD250×20 mm, Mobile phase: CO₂, EtOH+0.4% iPrNH₂). The pure fractions werecollected, evaporated until dryness and crystallized from pentane togive 450 mg of intermediate 230a and 500 mg of intermediate 230b

Preparation of Intermediate 231, Intermediate 231a and Intermediate 231b

Intermediate 231 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 and(R)-3-(A-Boc-A-methylamino)pyrrolidine as starting materials (1.03 g;89%). The separation of the enantiomers from 1.03 g of intermediate 231was performed via chiral SFC (Stationary phase: CHIRALPAK IC 250×30 mm,Mobile phase: 60% CO₂, 40% EtOH (0.3% iPrNH₂)). The pure fractions werecollected, evaporated until dryness and crystallized from pentane togive 481 mg (42%) of intermediate 231a and 435 mg (38%) of intermediate231b.

Preparation of intermediate 232:

Intermediate 232 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 291 andtert-butyl-1,4-diazepane-1-carboxylate as starting materials (228 mg,79%).

Preparation of Intermediate 233, Intermediate 233a and Intermediate 233b

Intermediate 233 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 234 and(S)-1-Boc-3-aminopyrrolidine as starting materials (845 mg; 82%). Theseparation of the enantiomers from 845 mg of intermediate 233 wasperformed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×30mm, Mobile phase: 60% CO₂, 40% EtOH (0.3% iPrNH₂)). The pure fractionswere collected, evaporated until dryness and crystallized from pentaneto give 357 mg (35%) of intermediate 233a and 305 mg (31%) ofintermediate 48.

Preparation of Intermediate 234

Intermediate 234 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 234 and(R)-2-(Aminoethyl)-1-Boc-pyrrolidine as starting materials (0.65 g,87%).

Preparation of Intermediate 235, Intermediate 235a and Intermediate 235b

Intermediate 235 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 378 asstarting material (805 mg; 98%). The separation of the enantiomers from805 mg of intermediate 235 was performed via chiral SFC (Stationaryphase: CHIRALPAK DIACEL 250×20 mm, Mobile phase: 70% CO₂, 30% EtOH (0.4%iPrNH₂)). The pure fractions were collected and evaporated until drynessto give 158 mg (20%) of intermediate 235a and 150 mg (19%) ofintermediate 235b.

Preparation of Intermediate 236, Intermediate 236a and Intermediate 236b

To a solution of compound 311 (150 mg; 0.347 mmol),N-(2-aminoethyl)-N-methylL carbamic acid tert-butyl ester (74 μL; 0.417mmol; 1.2 eq.) and DIPEA (120 μL; 0.695 mmol) in DMF (3 mL) was addedCOMU (223 mg; 0.521 mmol). The solution was stirred at rt for 18 h.Additional N-(2-aminoethyl)-N-methylL carbamic acid tert-butyl ester(18.6 μL; 0.104 mmol; 0.3 eq) was added and the solution was stirred atrt for 1 h. The crude was combined with another reaction performed on 50mg of compound 311. Water and EtOAc were added. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (3×). Thecombined organic layers were washed with a saturated aqueous solution ofNaCl (3×), dried over MgSO₄, filtered off and evaporated in vacuo. Thecrude (485 mg) was purified by silica gel chromatography (Stationaryphase: irregular bare silica 40 g, Mobile phase: 0.2% NH₄OH, 98% DCM, 2%MeOH) to give 294 mg of intermediate 236 as a yellow oil. The separationof the enantiomers from 294 mg of intermediate 236 was performed bychiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobilephase: 55% CO₂, 45% MeOH) to give 116 mg (43%) of intermediate 236a as ayellow film and 115 mg (42%) of intermediate 236b as a yellow film.

Preparation of Intermediate 242

Intermediate 242 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 170 andtert-butyl-1,4-diazepane-1-carboxylate as starting materials (465 mg,82%)

Preparation of Intermediate 246, Intermediate 246a and Intermediate 246b

Intermediate 246 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 236, using compound 378 and(S)-1-Boc-(methylamino)pyrrolidine as starting materials (600 mg).

The separation of the enantiomers from 600 mg of intermediate 246 wasperformed by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30mm, Mobile phase: 60% CO2, 40% EtOH) to give 210 mg (37%) ofintermediate 246a as a yellow film and 223 mg (40%) of intermediate 246bas a yellow film.

Preparation of Intermediate 247, Intermediate 247a and Intermediate 247b

Intermediate 247 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 236, using compound 378 and(S)-tert-butylmethyl(pyrolidine-3-yl)carbamate as starting materials.

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 65% CO₂,35% EtOH (0.3% iPrNH₂)) to give 217 mg (39%) of intermediate 247a as ayellow foam and 209 mg (37%) of intermediate 247b as a yellow foam.

Preparation of Intermediate 248, Intermediate 248a and Intermediate 248b

Intermediate 248 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using compound 83a asstarting material (1.4 g; 78%). The separation of the enantiomers from1.4 g of intermediate 248 was performed via chiral SFC (Stationaryphase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH(0.3% iPrNH₂)). The pure fractions were collected and evaporated untildryness to give 563 mg (31%) of intermediate 248a and 551 mg (31%) ofintermediate 248b.

Example A35

Preparation of Intermediate 137:

Tributyl(l-ethoxy vinyl)tin (14.23 g; 39.40 mmol) was added to asolution of intermediate 60 (9.12 g; 27.63 mmol) in anhydrous1,4-dioxane (250 mL) under N₂. Dichlorobis(triphenylphosphine) palladium(II) (0.97 g; 1.38 mmol) was added and the mixture was purged again withN₂. The reaction mixture was heated at 100° C. for 48 h. After coolingdown to rt, formic acid (30 mL) was added and the mixture was stirred atrt overnight. The mixture was slowly basified with a saturated solutionof NaHCO₃, then filtered and the filtrate was evaporated under vacuum.The residue (9 g) was washed with water (2×30 mL), ACN (3×30 mL) andevaporated under vacuum to give 5 g (64%) of intermediate 137.

Preparation of Intermediate 138:

Intermediate 138 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 15, using intermediate 137as starting material (310 mg, 68%).

Example A36

Preparation of Intermediate 140:

At 0° C., thionyl chloride (200 μL; 2.75 mmol) was added to a solutionof compound 84 (550 mg; 1.37 mmol) in DCM (25 mL). The solution wasallowed to warm to rt, stirred for 2 h and, then evaporated under vacuumto give 575 mg (100%) of intermediate 140. The crude product was usedwithout purification in the next step.

Preparation of Intermediate 142:

Intermediate 142 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 140, using compound 154a asstarting material (275 mg, quant.). The product was used withoutpurification in the next step.

Preparation of Intermediate 143:

Intermediate 143 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 140, using compound 154b asstarting material (234 mg, quant.). The product was used withoutpurification in the next step.

Example A37

Preparation of Intermediate 147:

At 0° C., a solution of di-tert-butyl dicarbonate (371 mg; 1.70 mmol) inTHF (5 mL) was added dropwise to a solution of2,2′-oxybis[A-methyl-ethanamine] (900 mg; 6.8 mmol) in THF (5 mL). Thereaction mixture was stirred at rt overnight. The reaction mixture waspoured into water, extracted with EtOAC. The organic layer was separatedand washed with brine, then dried over MgSO₄, filtered and evaporated togive 330 mg of (83%) of intermediate 147. The product was used withoutpurification in the next step.

Example A38

Preparation of Intermediate 150:

Under N₂ at 10° C., sodium hydride (72 mg; 1.80 mmol) was added to asolution of compound 154a (180 mg; 0.45 mmol) in DMF (2 mL). Thesolution was stirred at 10° C. for 30 min. Then,2-(2-bromoethoxy)tetrahydro-2H-pyran (85 μL; 0.54 mmol) was added andthe solution was allowed to slowly rise to rt for 5 h. The solution wascooled and the mixture was poured into cooled water. The product wasextracted with EtOAc. The organic layer was washed with water and driedover MgSO₄, filtered and evaporated to dryness. The residue (300 mg) waspurified by chromatography over silica gel (irregular bare silica 10 g;mobile phase: 95% DCM, 5% MeOH, 0.1% NH₄OH). The pure fractions werecollected and the solvent was evaporated to give 181 mg (76%) ofintermediate 150.

Preparation of Intermediate 151:

Intermediate 151 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 150, using compound 154b and2-(2-bromoethoxy)tetrahydro-2H-pyran as starting materials (238 mg;72%).

Example A39

Preparation of Intermediate 162 (Identical to Intermediate 179):

Intermediate 162 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 5, using intermediate 4 and2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-ethanamine as startingmaterials (9.6 g; 73%).

Preparation of Intermediate 163:

In a sealed tube, a mixture of intermediate 162 (1 g; 2.02 mmol),3,5-difluorobenzylamine (0.286 mL; 2.42 mmol) and Cs₂CO₃ (1.32 g; 4.04mmol) in tert-amyl alcohol (10 mL) was degased with N₂.2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (47 mg; 0.10mmol) and BrettPhos Precatalyst First Gen (80.6 mg, 0.101 mmol) wereadded. The reaction mixture was purged with N₂ and heated at 100° C. for18 h. Water and EtOAc were added. Then the mixture was extracted. Theorganic layer was separated, dried over MgSO₄, filtered and evaporated.The residue (1.3 g) was purified by chromatography over silica gel (40 gof SiOH 20-45 μm; gradient: from 100% DCM to 95% DCM, 5% MeOH, 0.1%NH₄OH). The pure fractions were collected and the solvent was evaporatedto give 780 mg (69%) of intermediate 163.

Preparation of Intermediate 164:

Intermediate 164 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162and 2-methyl-3-(trifluoromethyl)benzylamine as starting materials (670mg; 62%).

Preparation of Intermediate 165:

Intermediate 164 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162and 3-fluorobenzylamine as starting materials (765 mg; 63%).

Preparation of Intermediate 166:

Intermediate 166 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162and (RS)-1-(3,5-difluorophenyl)ethylamine as starting materials (700 mg;61%).

Preparation of Intermediate 203:

Intermediate 203 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163 using intermediate 202and intermediate 5 as starting materials (300 mg, 62%).

Preparation of Intermediate 204:

Intermediate 204 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162and intermediate 202 as starting material (410 mg, 88%)

Preparation of Intermediate 216:

Intermediate 216 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162as starting material and 2-Methyl-3-fluorobenzylamine (845 mg, 76%).

Preparation of Intermediate 218:

Intermediate 218 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 217as starting material and 3,5-difluorobenzylamine (310 mg, 66%).

Preparation of Intermediate 219:

intermediate 219 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162as starting material and 2-methyl-5-fluorobenzylamine (420 mg, 75%).

Preparation of Intermediate 240:

Intermediate 240 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163 using intermediate 239and 3-Fluoro-2-methylbenzylamine as starting materials (450 mg, 81%).

Preparation of Intermediate 243:

Intermediate 243 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 239and 3,5-difluorobenzylamine as starting materials (460 mg, 82%).

Preparation of Intermediate 245:

Intermediate 245 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 162and 2-(4-Fluorophenyl)azetidine as starting materials (700 mg, 61%).

Example A40

Preparation of Intermediate 174:

Intermediate 174 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 162 and2-(2R)-2-(3,5-difluorophenyl)pyrrolidine as starting materials, (200 mg;33%) of intermediate 174.

Preparation of Intermediate 175:

Intermediate 175 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 162 and2-(2S)-2-(3,5-difluorophenyl)pyrrolidine as starting materials, (260 mg;43%) of intermediate 175.

Example A41

Preparation of Intermediate 176:

Titanium(IV) ethoxide (2.66 mL, 12.68 mmol) was added dropwise to asolution of intermediate 10a (1 g, 3.17 mmol) and(R)-(+)-2-methyl-2-propanesulfmimide (0.672 g, 5.55 mmol) in THF (25 mL)at room temperature under N₂. The solution was refluxed for 24 h. Themixture was poured into brine and DCM was added. The precipitate wasfiltered through a short pad of Celite® which was washed with DCM. Theorganic layer was separated, dried over MgSO₄, filtered and evaporateduntil dryness. The residue (1.5 g) was purified by chromatography oversilica gel (40 g of SiOH 15-40 μm; gradient: from 100% DCM to 95% DCM,5% MeOH). The pure fractions were collected and the solvent wasevaporated to give 600 mg (44%) of intermediate 176.

Alternative Preparation of Intermediate 176:

Titanium (IV) ethoxide (26.59 mL, 126.85 mmol) was added dropwise to asolution of intermediate 10a (10 g, 31.71 mmol) and(R)-(+)-2-methyl-2-propanesulfinamide 99% (7.68 g, 63.43 mmol) incyclopentyl methyl ether (100 mL) at room temperature under N₂. Thesolution was refluxed for 3 h. The mixture was poured into brine and DCMwas added. The precipitate was filtered through a short pad of Celite®and washed with DCM. The organic layer was separated, dried over MgSO₄,filtered and evaporated until dryness. The residue was crystallized fromDIPE. The precipitate was filtered off and dried under vacuum to yield13.03 g (y=95%, de=96.9) of intermediate 176.

Preparation of Intermediate 177a and Intermediate 177:

Sodium cyanoborohydride (1.1 g, 17.6 mmol) and acetic acid (2.01 mL,35.14 mmol) were added to a solution of intermediate 176 (3.8 g, 8.78mmol) in MeOH (50 mL) and DCM (50 mL) at −15° C. The solution wasstirred at −15° C. for 5 h. The mixture was poured into water, basifiedwith a 10% aqueous solution of K₂CO₃ and the resulting aqueous mixturewas extracted with DCM. The combined organic layers were washed withbrine (2×), dried over MgSO₄, filtered and evaporated. The residue (5.2g) was purified by silica gel chromatography (Irregular SiOH 15-40 μm,80 g; gradient from 100% DCM to 95% DCM, 5% MeOH). The pure fractionswere collected and the solvent was evaporated until dryness to give 2.26g of a mixture of intermediates 177 and 177a (40/60 by LCMS).

Preparation of Intermediate 177:

Manganese dioxide (0.876 g, 10.08 mmol) was added portionwise to asolution of intermediate 177a (1.1 g, 2.52 mmol) in DCM (40 mL) at roomtemperature. The mixture was stirred at rt for 3 h. The mixture wasfiltered through a pad of Celite®, washed with DCM and the solvent wasevaporated to dryness to give 1.34 g (100%) of intermediate 177 (de:90%).

Preparation of intermediate 178:

To a solution of intermediate 177 (1.34 g, 3.08 mmol) in ACN (20 mL) wasadded hydrochloric acid in 1,4-Dioxane 4M (0.77 mL, 3.08 mmol). Themixture was stirred at rt for 1 h. The mixture was basified with asaturated aqueous solution of NaHCO₃. The aqueous layer was extractedwith DCM (3×). The combined organic layers were dried over MgSO₄,filtered off and evaporated. The residue (1.5 g) was purified by silicagel chromatography (Irregular SiOH 15-40 μm 40 g; gradient from 100% DCMto 90% DCM, 10% MeOH). The pure fractions were collected and the solventwas evaporated until dryness to give 840 mg (82%) of intermediate 178(ee: 89.6%).

Example A42

Preparation of Intermediate 179 (Identical to Intermediate 162):

At 10° C., HBTU (10.093 g, 26.615 mmol) was added portion wise to amixture of intermediate 4 (9 g, 26.615 mmol), MN-Di isopropyl ethylamine (11.621 mL, 66.536 mmol) and 2-(t-butyldimethylsilyl)oxyethanamine(7 g, 39.922 mmol) in DMF (165 mL). The reaction mixture was stirred for18 h. H₂O and EtOAc were added. The reaction mixture was extracted andthe organic layer was separated, dried over MgSO₄, filtered andconcentrated to give 22 g of a intermediate residue which was taken upwith DCM. The precipitate was filtered. The mother layer wasconcentrated and purified by silica gel chromatography (330 g of SiO₂,20-45 μm, gradient from 100% DCM to 95% DCM 5% MeOH 0.1% NH₄OH). Thepure fractions were collected and evaporated until dryness to afford 9.6g (73%) of intermediate 179.

Preparation of Intermediate 180:

In a sealed tube, a mixture of intermediate 179 (1 g, 2.02 mmol),3-fluoro-2-methylbenzylamine (0.262 mL, 2.0 mmol) and Cs₂CO₃ (1.315 g,4.036 mmol) in tert-amyl alcohol (10 mL) was degassed with N₂.2-Dicyclohexyphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (47.09 mg, 0.101mmol) and BrettPhos Precatalyst First Gen (80.6 mg, 0.101 mmol) wereadded. The reaction mixture was purged with N₂ and heated at 100° C. for18 h. H₂O and EtOAc were added. The reaction mixture was extracted. Theorganic layer was separated, dried over MgSO₄, filtered and concentrate.The residue (1.35 g) was purified by silica gel chromatography (40 g ofSiO₂, 20-45 μm, gradient from 100% DCM to 90% DCM 10% MeOH 0.1% NH₄OH).The pure fractions were collected and evaporated until dryness to afford845 mg (76%) of intermediate 180 which was directly used in the nextsteps without any further purification.

Example A43

Preparation of Intermediate 181:

3-fluoroaniline was treated with 4-nitrophenyl sulfonyl chloride indichloromethane using pyridine as the base. The procedure was executedon 100 and 300 g scale of fluoroaniline in 90% average yield.

Preparation of Intermediate 182:

Intermediate 15b (1.0 eq.) and intermediate 181 (1.5) were dissolved inTHF (10 volumes). Then, at 0° C., tributylphosphine (n-Bu₃P) (3-4equivalents) and di-iso-propyl azodicarboxylate (DIAD) (3-4 equivalents)were added. The reaction is exothermic and keeping the temperature at 0°C. during the additions proved to be a critical parameter to avoid asignificant decrease in e.e. (racemic material was obtained when thetemperature was allowed to raise to 35° C. during the DIAD addition).After complete addition of the reagents, the temperature was increasedto 30° C. and, after complete conversion (typically 16 hours), water wasadded. The solvent was switched to DCM for washing and extraction. DCMwas then evaporated. The residue was slurried in 10 volumes of methanoland the precipitate was filtered. The procedure was respectivelyexecuted on 50 g scale of intermediate 15b with 3.0 equivalents of bothn-Bu₃P and DIAD to give intermediate 182 with a 76% yield (e.e.: 75.1and on 200 g scale of intermediate 15b with 4.0 equivalents of bothn-Bu₃P and DIAD to give intermediate 182 with a 56% yield (e.e.: 82.5%).

Example A44

Preparation of Intermediate 184:

Condensation of methyl 3,4-diaminobenzoate with diethyl oxalate (8.0equivalents) in toluene (10 volumes) was carried out at reflux for 88hours. After complete conversion, the mixture was concentrated to aresidue which was washed with MTBE. After drying intermediate 184 wasobtained in 90% yield.

Preparation of Intermediate 185:

Intermediate 184 was dissolved in 1,2-dichloroethane (10 volumes). Then,dimethylformamide was added (1.0 equivalent) followed by thionylchloride (4.0 equivalents). The mixture was heated to 80° C. for 3hours, cooled to 15° C. and water (5 volumes) was slowly added. Afterphase separation, the organic layer was washed twice with water (10volumes) and the solvent was exchanged to 2-Me-THF (15 volumes).Triethylamine was added (3.0 equivalents) followed by morpholine (1.0equivalents) and the reaction was stirred at room temperature. Aftercomplete conversion, water (10 volumes) was added and the layers wereseparated. Then, the aqueous phase was washed with 2-MeTHF (5 volumes).The combined organic layers were washed with water (5 volumes),concentrated to a residue to obtain a solid which was slurried in MTBE(5 volumes). The precipitate was filtered and dried to give intermediate185 in 70% yield.

Preparation of Intermediate 186:

Intermediate 185 was dissolved in dichloromethane (10 volumes) and1,8-diazabicyclo[5.4.0]undec-7-ene (2.0 equivalents) was added. Pd/C(10%, 50% wet, 7% mol) was added and the mixture was hydrogenated (50psi) for 24 hours. When the conversion was complete, the mixture wasfiltered through a pad of Celite® and, to the filtrate, MnO₂ (0.1equivalents) was added. The mixture was warmed to 30-40° C. thenfiltered again on Celite® and the filtrate was concentrated to 1-2volumes. The solvent was exchanged to methyl tertiobutylether (5-7volumes) and the mixture was cooled to 5-10° C. and stirred at the sametemperature for 2 hours. The solid was filtered and dried to obtainintermediate 186 in 86% yield (99.4% purity).

Example A45

Preparation of Intermediate 190:

A suspension of intermediate 5 (1.03 g, 2.72 mmol),Bis(Pinacolato)diboron) (1.38 g, 5.44 mmol) and potassium acetate (1.07g, 10.9 mmol) in 1,4-dioxane (10.5 mL) was degassed with nitrogen.Dichloro(diphenylphosphinoferrocene)palladium (99.5 mg, 0.136 mmol) wasadded and the mixture was heated to 100° C. overnight. The resultingsolution was cooled down to room temperature, concentrated under reducedpressure, taken up into brine (50 mL) and extracted with EtOAc (3×100mL). The combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (irregular SiOH, 15-40 μm, 50 g, mobile phasegradient: from DCM 100% to DCM 90%, MeOH 10%) to give a mixture ofintermediate 190 and intermediate 191 (905 mg, ratio 55/45) as an orangefoam.

Preparation of Intermediate 191:

Sodium Periodate (703 mg, 3.29 mmol) was added to a solution of amixture of intermediate 190 and intermediate 191 (903 mg, ratio 55/45)in THF (5.52 mL) and water (17.5 mL) and the mixture was stirred at roomtemperature for 1 h. (43.8 mL, 43.8 mmol) was added and the reactionmixture was stirred at room temperature for 1 h. The resulting solutionwas quenched with water (50 mL) and extracted with a mixture of DCM/MeOH(8/2, 3×100 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (irregular SiOH, 15-40 μm, 50 g,mobile phase gradient: from DCM 100% to DCM 90%, MeOH 10%) to give (780mg, 100%) of intermediate 191 as a light orange powder.

Example A46

Preparation of Intermediate 192:

In a Schlenk tube, a solution of intermediate 55a (1 g; 2.97 mmol),1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester(1.08 g; 3.87 mmol) and potassium carbonate (0.82 g; 5.95 mmol) in1,4-dioxane (15 mL) and water (3 mL) was degassed under nitrogen. Pd.Cl₂(dppf).DCM (244 mg; 0.3 mmol) was added and the reaction mixture washeated at 95° C. for 24 hours. The mixture was cooled to rt, The mixturewas poured into a mixture of water and EtOAc, then filtered through apad of Celite®. The aqueous layer was extracted with EtOAc, The organiclayer was washed with brine and dried over MgSO₄, filtered andevaporated to dryness, The resulting residue was taken-up with a mixtureof Pentane and Et₂O. The precipitate was filtered to afford 0.42 g (35%)of intermediate 192. The filtrate was evaporated to dryness to affordadditional 0.7 g (58%) of intermediate 192.

Preparation of Intermediate 193:

To a solution of intermediate 192 (0.42 g; 1.03 mmol) in MeOH (15 mL)and DCM (5 mL) was added sodium borohydride (43 mg; 1.13 mmol) and themixture was stirred at 10° C. for 2 h. Then, DCM and water were added.The layers were separated. The aqueous layer was extracted with DCM (2×)and the combined organic layers were dried over MgSO₄, filtered off andevaporated in vacuo. The crude (0.45 g) was purified by silica gelchromatography (Stationary phase: irregular SiOH 15-40 μm 300 g, Mobilephase: 45% Heptane, 50% AcOEt, 5% MeOH, 0.1% NH₄OH) yielding 200 mg(47%) of intermediate 193.

Preparation of Intermediate 194:

Intermediate 194 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 52, using intermediate 193(as starting material (directly used without purification for the nextstep).

Example A47

Preparation of Intermediate 197:

The reaction was performed twice on 12.17 g ofmethyl-2-bromo-3-fluorobenzoate and the different reaction mixtures weremixed for the work-up and the purification.

Under N₂, to a mixture of methyl-2-bromo-3-fluorobenzoate (24.34 g,104.45 mmol),tert-butyl-4-(4,4,5,5-tetramethyl-1,2,3,-dioxaborolan-2-yl)-5-6-dihydropyridine-1(2H)-carboxylate (48.44 g, 156.67 mmol) and K₃PO₄ (66.51 g, 313.34 mmol)in a mixture of 1,4-dioxane (250 mL) and distilled water (75 mL) wasadded [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II),complex with dichloromethane (4.27 g, 5.22 mmol). The reaction mixturewas heated to 100° C. overnight, poured out into water and filteredthrough a Celite® layer. The organic layer was extracted with DCM,separated, dried, filtered and concentrated to dryness. The residue(55.6 g) was purified by column chromatography on silica gel (IrregularSiOH, 15-40 μm, 220 g, mobile phase: 100% DCM). The fractions containingthe product were collected and the solvent was evaporated until dryness.The resulting residue (37.9 g) was crystallized from pentane and theprecipitate was filtered off and dried under vacuum to give 17.6 g (50%)of intermediate 197.

Preparation of Intermediate 198:

A mixture of intermediate 197 (16.50 g, 49.20 mmol) and Pearlman'scatalyst (1.40 g, 9.84 mmol) in MeOH (170 mL) was hydrogenated in a Parrreactor (2 atmospheres) for 12 h at room temperature. After removal ofH₂, the catalyst was filtered over a pad of Celite®, washed with DCM andthe filtrate was concentrated to give 16.4 g (99%) of intermediate 198.

Preparation of Intermediate 199:

Lithium aluminium hydride (1.85 g, 48.61 mmol) was added portionwise toa mixture of intermediate 198 (16.40 g, 48.61 mmol) in THF (200 mL) at5° C. under N₂. The mixture was stirred at 5° C. for 3 h. Then, EtOAcfollowed by water were added dropwise to the mixture at −5° C. Thesuspension was filtered through a pad of Celite®. The organic layer wasseparated, dried over MgSO₄, filtered and the solvent was evaporated togive 15.18 g (quantitative) of intermediate 199.

Preparation of Intermediate 200:

To a solution of intermediate 199 (9.23 g; 29.8) mmol) in DCM (100 mL)cooled to 0° C., was slowly added trimethylamine (6.22 mL; 44.7 mmol)followed by methasulfonylchoride (3.46 mL; 44.7 mmol). The mixture wasstirred at room temperature overnight. Water was added and the productwas extracted with DCM. The organic layer was dried over MgSO₄, filteredand concentrated till dryness. The residue was purified by silica gelchromatography (Irregular SiOH 15-40 μm 40 g, mobile phase: gradientfrom 80% Heptane, 20% AcOEt to 60% Heptane, 40% AcOEt). The purefractions were collected and the solvent was evaporated until dryness togive (9.1 g, 93%) of intermediate 200.

Preparation of Intermediate 201:

A mixture of intermediate 200 (3.15 g; 9.61 mmol), potassium phtalimide(1.87, 10.09 mmol) in DMF (24 mL) was stirred at room temperature for 3days. The insoluble was filtered off, washed with diethylether and driedto afford (4.3 g, 100%) of intermediate 201.

Preparation of Intermediate 202:

A mixture of intermediate 201 (4.3 g, 4.81 mmol), hydrazine monohydrate(2.2 mL, 35.87 mmol) in EtOH (142 mL) was heated to 80° C. for 3 h 30hours. The reaction mixture was cooled to room temperature andevaporated to dryness. DCM was added and the residue was stirred for 10min. The insoluble was filtered and washed with DCM. The filtrate waspurified by silica gel chromatography (12 g of SiOH 35-40 μm, gradientfrom 100% DCM to 80% DCM 20% CH3OH 0.1% NH₄OH). The fractions werecollected and evaporated until dryness to give (1.75 g, 58%) ofintermediate 202.

Example A48

Preparation of Intermediate 205:

TBAF (1M in THF, 0.624 mL, 0.624 mmol) was added dropwise to a solutionof intermediate 204 (0.41 g, 0.567 mmol) in THF (15 mL) at roomtemperature. The mixture was stirred for 3 h at room temperature. Thesolution was poured into ice water, extracted with EtOAc and washed withbrine. The organic layer was dried over MgSO₄, filtered and evaporatedto dryness to give 0.56 g of intermediate 205 which was directly used inthe next step.

Example A49

Preparation of Intermediate 210:

In a Schlenk reactor, a solution of intermediate 3a (5.00 g; 14.2 mmol),vinylboronic acid pinacolester (3.28 g; 21.3 mmol) and potassiumphosphate (4.52 g; 21.3 mmol) in dioxane (120 mL) and water (30 mL) waspurged with N₂. Then, PdCl₂(dppf).DCM (581 mg; 710 μmol) was added. Thereaction mixture was purged again with N₂ and heated at 90° C. for 4 h.After cooling down to rt, the reaction mixture was diluted with EtOAcand washed successively with water and a saturated aqueous solution ofNaCl. The organic layer was separated, dried over MgSO₄, filtered offand evaporated in vacuo. The residue (7.31 g) was purified by silica gelchromatography (Irregular SiOH 15-40 μm, 330 g, mobile phase: gradientfrom heptane 80%, EtOAc 20% to heptane 50%, EtOAc 50%) to give a paleyellow sticky solid which was triturated in Et₂O, the precipitate wasfiltered on a glass frit to give 2.32 g (55%) of intermediate 210 as apale yellow solid.

Preparation of Intermediate 211:

A solution of intermediate 210 (2.32 g; 7.75 mmol), osmium tetroxide2.5% in butanol (5.01 mL; 0.388 mmol), sodium periodate (5.80 g; 27.1mmol) in THF (115 mL) and water (45 mL) was stirred at rt for 18 h. Thereaction mixture was poured into ice water and EtOAc was added. Theorganic layer was separated, dried over MgSO₄, filtered off andevaporated in vacuo. The resulting residue was triturated in MeOH andthe solid was filtered on a glass frit and dried in vacuo to give 1.86 g(80%) of intermediate 211 as a yellow-brown solid.

Preparation of Intermediate 212:

In a sealed tube, 3-fluoro-2-methylaniline (530 μL; 4.64 mmol) andmolecular sieves 4 Å (4.60 g) were added to a solution of intermediate211 (700 mg; 2.32 mmol) in dry DCM (22 mL). The reaction mixture wasstirred at rt over the weekend. Additional molecular sieves 4 Å (1.20 g)was added and the mixture was stirred at rt for 20 h. Additional3-fluoro-2-methylaniline (132 μL; 1.16 mmol) and molecular sieves 4 Å(500 mg) were added and the mixture was again stirred at rt for 20 h.The mixture was filtered on a glass frit and the filtrate was evaporatedin vacuo to give 1.41 g of intermediate 212 as a yellow solid directlyused in the next step without any further purification.

Preparation of Intermediate 214:

Intermediate 214 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 212 using intermediate 211and 3,5-difluoroaniline as starting materials (516 mg, used withoutpurification in the next step).

Example A50

Preparation of Intermediate 239:

NaH (60% dispersion in mineral oil) (948.5 mg, 23.72 mmol) was addedportionwise to a solution of intermediate 238 (5.6 g, 10.7 mmol) in DMF(60 mL) under nitrogen cooled to 0-5° C. (ice bath cooling). The mixturewas stirred at 0-5° C. for 15 mn then iodomethane (1.41 mL, 22.59 mmol)was added. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was poured into water and the organic layer wasextracted with EtOAc. The crude residue (4.5 g) was purified by silicagel chromatography to afford 4 g (66%) of intermediate 239.

Preparation of Intermediate 241

Intermediate 241 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 239 using intermediate 240as starting material (19 mg, 4%).

Preparation of Intermediate 244

Intermediate 244 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 239 using intermediate 243as starting material (42 mg, 9%).

B. Preparation of the Final Compounds Example B1

Preparation of Compound 1, Compound 2 and Compound 26

In a sealed tube, a mixture of intermediate 9 (1.1 g; 3.10 mmol),l-bromo-3,5-difluorobenzene (0.53 mL; 4.64 mmol) and Cs₂CO₃ (4.03 g;12.38 mmol) in 1,4-dioxane (10 mL) was degazed under N₂. Xantphos (179mg; 0.31 mmol) and Pd(OAc)₂ (69 mg; 0.31 mmol) were added. The reactionmixture was heated at 100° C. for 5 h. The reaction mixture was pouredinto ice-water. EtOAc was added and the mixture was filtered through apad of Celite®. The filtrate was separated and the organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated. Theresidue (1.54 g) was purified by chromatography over silica gel(irregular bare silica 150 g; mobile phase: 0.2% NH₄OH, 98% DCM, 2%MeOH). The pure fractions were collected and the solvent was evaporatedto give 400 mg (28%) of compound 26. Compound 26 was purified by chiralSFC (CHIRALPAK AD-H; 5 μm 250×20 mm; mobile phase: 60% CO₂, 40% EtOH).The pure fractions were collected and the solvent was evaporated to give2 fractions:

Fraction 1: 178 mg which was dissolved in ACN. Then, Et₂O and heptanewere added. A precipitate was filtered and dried to give 105 mg (7%) ofcompound 1. M.P.: 100° C. (K).

Fraction 2: 170 mg which was dissolved in ACN. Then, ECO and heptanewere added. A precipitate was filtered and dried to give 93 mg (12%) ofcompound 2. M.P.: 100° C. (K).

Preparation of Compound 3 and Compound 4

In a sealed vessel, l-bromo-3,5-difluorobenzene (0.137 mL; 1.20 mmol)and Cs₂CO₃ (779 mg; 2.39 mmol) were added to a solution of intermediate37 (300 mg; 0.80 mmol) in 1,4-dioxane (8 mL). The mixture was carefullydegassed under vacuum and back-filled with N₂ (3×). Then, Pd(OAc)₂ (18mg; 0.08 mmol) and xantphos (92 mg; 0.16 mmol) were added and themixture was again carefully degassed under vacuum and back-filled withN₂ (3×). The reaction mixture was stirred at 100° C. overnight. Themixture was filtered through a pad of Celite®. The cake was washed withDCM/MeOH (9/1) and the filtrate was evaporated under vacuum. The residuewas taken-up with DCM and washed with an aqueous solution of NaHCO₃. Thelayers were separated and the aqueous layer was extracted with DCM (2×).The combined organics layers were dried over MgSO₄, filtered andevaporated under vacuum. The residue (512 mg, green foam) was purifiedby chromatography over silica gel (Spherical bare silica; 5 μm 150×30.0mm; gradient: from 98% DCM, 2% MeOH (+10% NH₄OH) to 90% DCM, 10% MeOH(+10% NH₄OH)). The pure fractions were collected and the solvent wasevaporated. The residue (148 mg, green oil) was purified by achiral SFC(CHIRALPAK AD-H; 5 μm 250×20 mm; mobile phase: 70% CO₂, 30% EtOH (0.3%iPrNH₂)). The pure fractions were collected and the solvent wasevaporated to give 2 fractions which were freeze-dried with water-ACN togive respectively 48 mg (13%, pale yellow fluffy solid) of compound 4and 53 mg (14%, pale yellow fluffy solid) of compound 3.

Preparation Compound 7, Compound 8 and Compound 9

In a sealed tube, a mixture of intermediate 44 (130 mg; 0.35 mmol),l-bromo-3,5-difluorobenzene (48 μL; 0.42 mmol) and Cs₂CO₃ (228 mg; 0.70mmol) in 2-methyl-2-butanol (1.70 mL) was purged with N₂. BrettPhosPrecatalyst First Gen (14 mg; 17.5 μmol) was added. The reaction mixturewas purged with N₂ and heated at 110° C. for 18 h. After cooling down tort, additional 1-bromo-3,5-difluorobenzene (48 μL; 0.42 mmol) and Cs₂CO₃(228 mg; 0.70 mmol) were added. The mixture was purged with N₂ andBrettPhos Precatalyst First Gen (14 mg; 17.5 μmol) was added. Themixture was purged with N₂ and heated at 110° C. for 18 h. After coolingdown to rt, the crude was combined with another batch coming from areaction performed on 20 mg of intermediate 44. EtOAc and water wereadded. The organic layer was separated. The aqueous layer wasneutralized with solid NH₄Cl and extracted with EtOAc (2×). The combinedorganic layers were dried over MgSO₄, filtered and evaporated undervacuum. The residue (277 mg, brown oil) was purified by chromatographyover silica gel (Irregular SiOH 15-40 μm; 10 g; gradient: from 100% DCMto 90% DCM, 10% acetone). The pure fractions were collected and thesolvent was evaporated to give a yellow oil which was triturated inEt₂O. The precipitate was filtered and dried under vacuum to give 122 mg(62%, yellow foam) of compound 7. M.P.: 206° C. (DSC).

86 mg of compound 7 was purified by chiral SFC (CHIRALCEL OJ-H; 5 μm250×20 mm; mobile phase: 75% CO₂, 25% MeOH). The pure fractions werecollected and the solvent was evaporated affording two fractions whichwere freeze-dried with water-ACN to give respectively 39 mg (20%, paleyellow fluffy solid) of compound 8 and 41 mg (21%, pale yellow fluffysolid) of compound 9.

Alternative Pathway:

In a sealed tube, a mixture of intermediate 45 (1.5 g; 20.91 mmol) and3,5-difluoroaniline (1.9 g; 14.53 mmol) in DMF (250 mL) was stirred at50° C. for 48 h. The solution was poured into ice-water. EtOAc was addedand the mixture was filtered through a pad of Celite®. The product wasextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand evaporated to dryness. The residue (200 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 40 g; mobile phase:0.1% NH₄OH, 98% DCM, 2% MeOH). The pure fractions were collected and thesolvent was evaporated to give 460 mg of compound 7.

260 mg of compound 7 were purified by chiral SFC (CHIRALCEL OJ-H 5 μm250×20 mm; mobile phase: 75% CO₂, 25% MeOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 111 mgof compound 8 (pure at 88% by ¹H NMR) and 102 mg of compound 9. 111 mgof compound 8 was purified by achiral SFC (CYANO 6 μm 150×21.2 mm;mobile phase: 85% CO₂, 15% MeOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated. The residue (98 mg) wascrystallized with pentane and Et₂O. The precipitate was filtered anddried to give 49 mg of compound 8. M.P.: 100° C. (gum, K).

Preparation Compound 11, Compound 12 and Compound 13

In a sealed tube, a mixture of intermediate 19 (283 mg; 0.86 mmol),l-bromo-3,5-difluorobenzene (147 μL; 1.29 mmol) and Cs₂CO₃ (560 mg; 1.72mmol) in 2-methyl-2-butanol (4.20 mL) was purged with N₂. BrettPhosPrecatalyst First Gen (34 mg; 43 μmol) and BrettPhos (9 mg; 17 μmol)were added. The reaction mixture was purged with N₂ and heated at 110°C. for 18 h. After cooling down to rt, l-bromo-3,5-difluorobenzene (147μL; 1.29 mmol) and Cs₂CO₃ (560 mg; 1.72 mmol) were added. The mixturewas purged with N₂ and BrettPhos Precatalyst First Gen (34 mg; 43 μmol)and BrettPhos (9 mg; 17 μmol) were added. The reaction mixture waspurged with N₂ and heated at 110° C. for 18 h. After cooling down to rt,the crude was diluted with EtOAc and filtered through a pad of Celite®.The filtrate was evaporated under vacuum to dryness. The residue (700mg, brown oil) was purified by chromatography over silica gel (IrregularSiOH 15-40 μm; 30 g; gradient: from 100% DCM to 95% DCM, 5% (iPrOH/NH₄OH90/10)). The pure fractions were collected and the solvent wasevaporated to give yellow oil which was triturated with diethylether anddried in vacuum to give 323 mg (85%, pale yellow solid) of compound 11(M.P.: 228° C. (DSC)). Compound 11 was purified by chiral SFC (CHIRALCELOJ-H 5 μm 250×20 mm; mobile phase: 80% CO₂, 20% MeOH). The purefractions were collected and the solvent was evaporated to give twofractions which were triturated with Et₂O, evaporated and dried undervacuum to give 116 mg (28%, off-white solid) of compound 12 (M.P.: 218°C. (DSC)) and 117 mg (28%, off-white solid) of compound 13 (M.P.: 217°C. (DSC)).

Preparation Compound 23 Compound 24 and Compound 25

In a sealed tube, a mixture of intermediate 64 (360 mg; 1.26 mmol),l-bromo-3,5-difluorobenzene (216 μL; 1.89 mmol) and sodium tert-butoxide(242 mg; 2.52 mmol) in 1,4-dioxane (13 mL) was degazed under N₂. Then,2-(di-tert-butylphosphino)biphenyl (38 mg; 0.13 mmol) and Pd₂(dba)₃ (58mg; 0.06 mmol) were added and the reaction mixture was heated at 100° C.for 18 h. The mixture was poured into water and filtered through a padof Celite®. The organic layer was extracted with DCM, separated, driedover MgSO₄, filtered and evaporated to dryness. The residue (400 mg) waspurified by chromatography over silica gel (SiOH 15 μm; gradient: from100% DCM to 95% DCM, 5% MeOH, 0.1% NH₄OH). The pure fractions werecollected and the solvent was evaporated. The residue (300 mg) was takenup with DIPE/CAN (drops). A solid was filtered and dried to give 160 mg(32%) of compound 23. Compound 23 was purified by chiral SFC (CHIRALCELOD-H 5 μm 250×20 mm; mobile phase: 70% CO₂, 30% iPrOH (0.3% iPrNH₂)).The pure fractions were collected and the solvent was evaporated to give64 mg (13%) of compound 24 (M.P.: 100° C. (gum, K)) and 70 mg (14%) ofcompound 25 (M.P.: 98° C. (gum, K)).

Preparation of Compound 27:

Compound 27 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 9 andbromobenzene as starting materials (30 mg, 16%). M.P.: 80° C. (gum, K).

Preparation of Compound 28:

Compound 28 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 9 and1-bromo-3-fluorobenzene as starting materials (46 mg, 24%). M.P.: 80° C.(gum, K).

Preparation Compound 29 and Compound 30

Compound 29 and compound 30 were prepared according to an analogousprocedure as described for the synthesis of compound 3, usingintermediate 37 and 1-bromo-3-fluorobenzene as starting material. Theracemic compound was purified by achiral SFC (CHIRALPAK AD-H 5 μm 250×20mm; mobile phase: 60% CO₂, 40% MeOH (0.3% iPrNH₂)). The pure fractionswere collected and the solvent was evaporated to give two fractionswhich were freeze-dried with water-ACN to give respectively 39 mg (11%,pale green fluffy solid) of compound 29 and 33 mg (9%, pale green fluffysolid) of compound 30.

Preparation of Compound 31:

Compound 31 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 25 and1-bromo-3,5-difluorobenzene as starting materials (300 mg, 13%). M.P.:213° C. (DSC).

Preparation of Compound 32:

Compound 32 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 9 and3-bromo-5-fluoroanisole as starting materials (85 mg, 25%). M.P.: 80° C.(gum, K).

Preparation of Compound 35:

Compound 35 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 9 and3-bromo-5-fluorotoluene as starting materials (83 mg, 25%). M.P.: 80° C.(gum, K).

Preparation of Compound 36:

Compound 36 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 71 and1-bromo-3,5-difluorobenzene as starting materials (90 mg, 34%). Compound36 was obtained as a mixture of 3 diastereoisomers.

Preparation of Compound 41:

Compound 41 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1, using intermediate 9 and3-bromoanisole as starting materials (freeze-dried, 16 mg, 3%). M.P.:80° C. (gum, K).

Preparation of Compound 42:

Compound 42 was prepared according to an analogous procedure asdescribed for the synthesis of compound 23, using intermediate 9 and4-bromofluorobenzene as starting materials (freeze-dried, 69 mg, 27%).M.P.: 80° C. (gum, K).

Preparation of Compound 44:

Compound 44 was prepared according to an analogous procedure asdescribed for the synthesis of compound 23, using intermediate 9 and3-bromo-5-fluorobenzaldehyde as starting materials (95 mg, 24%). M.P.:80° C. (gum, K).

Preparation Compound 52:

In a sealed tube, a mixture of intermediate 9 (100 mg; 0.28 mmol),3-bromobenzotrifluoride (95 mg; 0.42 mmol) and Cs₂CO₃ (183 mg; 0.56mmol) in 1,4-dioxane (3 mL) was degazed under N₂. Then,2-(di-tert-butylphosphino)biphenyl (17 mg; 0.06 mmol) and Pd₂(dba)₃ (26mg; 0.03 mmol) were added and the reaction mixture was heated at 100° C.for 24 h. The mixture was poured into water and filtered through a padof Celite®. The organic layer was extracted with DCM, separated, driedover MgSO₄, filtered and evaporated to dryness. The residue (180 mg) waspurified by chromatography over silica gel (Spherical bare silica 5 μm;150×30.0 mm; gradient: from 98% DCM, 2% MeOH (+10% NH₄OH) to 92% DCM, 8%MeOH (+10% NH₄OH)). The pure fractions were collected and the solventwas evaporated. The residue (33 mg) was freeze-dried with water/ACN80/20 to give 32 mg (23%) of compound 52. M.P.: 80° C. (gum, K).

Preparation compound 54:

Compound 54 was prepared according to an analogous procedure asdescribed for the synthesis of compound 52, using intermediate 9 and4-bromo-2-fluorobenzonitrile as starting materials (freeze-dried: 37 mg,28%). M.P.: 80° C. (gum, K).

Preparation Compound 55:

Compound 55 was prepared according to an analogous procedure asdescribed for the synthesis of compound 52, using intermediate 9 and2-bromo-2-methyl-3-(trifluoromethyl)benzene as starting materials(freeze-dried: 16 mg, 11%). M.P.: 80° C. (gum, K).

Preparation Compound 57:

Compound 57 was prepared according to an analogous procedure asdescribed for the synthesis of compound 52, using intermediate 81 and1-bromo-3,5-difluorobenzene as starting materials (freeze-dried: 31 mg,24%, white powder). M.P.: 80° C. (gum, K).

Preparation Compound 58:

Compound 58 was prepared according to an analogous procedure asdescribed for the synthesis of compound 52, using intermediate 82 and1-bromo-3,5-difluorobenzene as starting materials (freeze-dried: 36 mg,28%, white powder). M.P.: 80° C. (gum, K).

Preparation Compound 85:

Compound 85 was prepared according to an analogous procedure asdescribed for the synthesis of compound 11, using intermediate 14 and1-bromo-3-fluorobenzene as starting materials (freeze-dried: 36 mg, 29%,pale yellow fluffy solid).

Preparation of Compound 106 and Compound 107

Compound 106 and compound 107 were prepared according to an analogousprocedure as described for the synthesis of compound 52, usingintermediate 114 and 1-bromo-3,5-difluorobenzene as starting materials.The residue (0.6 g) was purified by chromatography over silica gel(irregular 15-40 μm; 40 g; mobile phase: 50% heptane, 50% EtOAc). Thepure fractions were collected and the solvent was evaporated. Theresidue (160 mg) was purified by chiral SFC (CHIRALCEL OD-H 5 μm; 250×20mm; mobile phase: 80% CO₂, 20% EtOH (0.3% iPrNH₂)). The pure fractionswere collected and the solvent was evaporated to give 57 mg (10%) ofcompound 106 (M.P.: 80° C., gum, K) and 60 mg (10%) of compound 107(M.P.: 80-90° C., gum, K).

Preparation Compound 249:

The experiment was performed 4 times on the same quantity (580 mg; 1.46mmol) of intermediate 24.

In a sealed tube, a mixture of intermediate 24 (580 mg; 1.46 mmol),l-bromo-3,5-difluorobenzene (0.29 mL; 2.54 mmol) and Cs₂CO₃ (1.1 g; 3.39mmol) in 1,4-dioxane (20 mL) was degazed under N₂.2-(di-tert-butylphosphino)biphenyl (101 mg; 0.34 mmol) and Pd₂(dba)₃(155 mg; 0.17 mmol) were added. The reaction mixture was heated at 100°C. for 48 h. The reaction mixture was poured into ice-water and EtOAcwas added, filtered through a pad of Celite®. The filtrate was separatedand the organic layer was dried over MgSO₄, filtered and evaporated. Theresidue (4 g) was purified by chromatography over silica gel (irregular15-40 μm 120 g; mobile phase: 65% heptane, 35% EtOAc). The purefractions were collected and the solvent was evaporated to give 950 mg(31%) of compound 249. M.P.: 211° C. (DSC).

Preparation of Compound 252:

In a sealed tube, a mixture of intermediate 25 (1.73 g; 5.05 mmol),l-bromo-3,5-difluorobenzene (750 μL; 6.57 mmol) and Cs₂CO₃ (2.47 g; 7.58mmol) in 1,4-dioxane (16 mL) was degazed under N₂. Xantphos (292 mg;0.51 mmol) and Pd₂(dba)₃ (231 mg; 0.25 mmol) were added. Then, thereaction mixture was heated at 100° C. overnight. The mixture was pouredinto H₂O, filtered through a pad of Celite® and extracted with EtOAc.The organic layer was dried over MgSO₄, filtered and evaporated untildryness. The residue (1.5 g) was purified by chromatography over silicagel (irregular 15-40 μm; 80 g; mobile phase: 65% heptane, 35% EtOAc).The pure fractions were collected and the solvent was evaporated to give1.04 g (60%) of intermediate 25 and an intermediate residue was taken-upwith Et₂O The precipitate was filtered and dried under vacuum to give300 mg (13%) of compound 252.

Preparation of Compound 254:

The experiment was performed 12 times on the same quantity (475 mg; 1.39mmol) of intermediate 23:

Compound 254 was prepared according to an analogous procedure asdescribed for the synthesis of compound 249, using intermediate 23 and1-bromo-3,5-difluorobenzene as starting materials (1.7 g, 22%).

Preparation of Compound 255:

Compound 255 was prepared according to an analogous procedure asdescribed for the synthesis of compound 249, using intermediate 9 and2-bromo-4-fluorobenzaldehyde as starting materials (120 mg, 22%).

Preparation of Compound 274:

In a sealed tube, a mixture of intermediate 178 (0.2 g; 0.605 mmol),l-bromo-3-fluorobenzene (0.079 mL; 0.726 mmol) and Cs₂CO₃ (0.394 g; 1.21mmol) in tert-amyl alcohol (3 mL) was degased with N₂. BrettPhosPrecatalyst First Gen (24 mg, 0.0303 mmol) and Brettphos (6.5 mg; 0.012mmol) were added. The reaction mixture was purged with N₂ and heated at110° C. for 42 h. After cooling down to rt, the crude was poured intowater, diluted with EtOAc and filtered on a pad of Celite®. The aqueouslayer was acidified and extracted with DCM, the combinated layers weredried over MgSO₄, filtered and evaporated to give 94 mg (39%) of thecompound 274 (ee: 90%).

Alternative Preparation of Compound 274:

Compound 262a was hydrolyzed in THF (10 volumes) using NaOH (1.0 M inwater, 4 eq.) at 50° C. for 16 hours. The product was isolated bydistillation of THF, dilution with water and pH adjustment to 6-7 with2M HCl. The procedure was executed on 18 and 100 g scale of compound262a and gave compound 274 in quantitative yield (e.e.: 97.9%.

Preparation of Compound 350:

Compound 350 was prepared according to an analogous procedure asdescribed for the synthesis of compound 52, using intermediate 24 and4-bromo-1,2-difluorobenzene as starting materials (250 mg, 19%).

Example B2

Preparation of Compound 84:

A solution of thioglycolic acid (24 μL; 0.34 mmol) and1,8-diazabicyclo(5.4.0)undec-7-ene (102 μL; 0.68 mmol) in ACN (2 mL) wasadded to a solution of intermediate 100 (100 mg; 0.17 mmol) in ACN (3mL). The solution was stirred at rt for 15 min then DCM and 10% aqueoussolution of Na₂CO₃ were added. The organic layer was separated and theaqueous layer was extracted with DCM (2×). The combined organic layerswere dried over MgSO₄, filtered and evaporated in vacuum. The residue(60 mg) was purified by chromatography over silica gel (irregular baresilica 40 g; mobile phase: 0.4% NH₄OH, 96% DCM, 4% MeOH). The purefractions were collected and the solvent was evaporated. The residue (36mg) was purified by reverse phase (X-Bridge-C18; 5 μm 30*150 mm;gradient: from 75% NH₄HCO₃ 0.5%, 25% ACN to 35% NH₄HCO₃ 0.5%, 65% ACN).The pure fractions were collected and the solvent was evaporated to give30 mg (44%) of compound 84. M.P.: 80° C. (gum, K).

Preparation of Compound 100:

Compound 100 was prepared according to an analogous procedure asdescribed for the synthesis of compound 84, using intermediate 108 asstarting material (75 mg, 82%, pale yellow solid.

Preparation of Compound 136

Compound 136 was prepared according to an analogous procedure asdescribed for the synthesis of compound 84, using intermediate 128 asstarting material (39 mg, 44%, off-white solid. M.P.: 184° C. (DSC).

Example B3

Preparation Compound 15 and Compound 16

At 10° C., methylmagnesium bromide (0.27 mL; 0.82 mmol) was added to asolution of compound 250 (0.29 g; 0.68 mmol) in THF (8 mL) under N₂. Thesolution was stirred at 10° C. for 45 min. The solution was poured intoa saturated NH₄Cl solution and the product was extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered and evaporated to dryness.The residue (285 mg) was purified by chromatography over silica gel(irregular 15-40 μm; 12 g; mobile phase: 96% DCM, 4% MeOH, 0.1% NH₄OH).The pure fractions were collected and the solvent was evaporated to give158 mg of fraction 1 and 56 mg of fraction 2. Fraction 1 was purified byreverse phase (X-Bridge-C18 5 μm 30*150 mm; gradient: from 65% NH₄HCO₃0.5%, 35% ACN to 25% NH₄HCO₃ 0.5%, 75% ACN). The pure fractions werecollected and the solvent was evaporated. The residue (103 mg) wascombined with 56 mg of fraction 2 to give 159 mg which were purified byachiral SFC (CHIRALPAK IC 5 μm 250×20 mm; mobile phase: 70% CO₂, 30%iPrOH (0.3% iPrNH₂)). The pure fractions were collected and the solventwas evaporated to give two fractions which were freeze-dried withwater-ACN (80/20) to give 70 mg (23%, yellow powder) of compound 15(M.P.: 80° C. (gums, K)) and 56 mg (15%, yellow powder) of compound 16(M.P.: 80° C. (gums, K)).

Example B4

Preparation Compound 17:

At 0° C., HCl (4M in 1,4-dioxane) (0.31 mL; 1.26 mmol) was added to asolution of intermediate 49 (150 mg; 0.25 mmol) in ACN (6 mL). Thereaction mixture was stirred at 0° C. for 1 h and at rt for 3 h. Thesolution was poured into ice-water and extracted with EtOAc. The organiclayer was dried over MgSO₄, filtered and the solvent was evaporated. Theresidue (160 mg) was purified by chromatography over silica gel(irregular bare silica 40 g; mobile phase: 0.1% NH₄OH, 90% DCM, 10%MeOH). The pure fractions were collected and the solvent was evaporateduntil dryness to give 45 mg (36%) of compound 17. M.P.: 170° C. (K).

Preparation Compound 18:

At 0° C., HCl (4M in 1,4-dioxane) (0.92 mL; 3.68 mmol) was added to asolution of intermediate 50 (450 mg; 0.74 mmol) in DCM (5 mL). Thereaction mixture was stirred at 0° C. for 1 h and at rt for 3 h. Thesolution was poured into ice-water and extracted with EtOAc. The organiclayer was dried over MgSO₄, filtered and the solvent was evaporated. Theresidue (265 mg) was purified by chromatography over silica gel(irregular 15-40 μm; 24 g; mobile phase: 60% heptane, 5% MeOH, 35%EtOAc). The pure fractions were collected and the solvent was evaporatedto give 132 mg (35%, yellow foam) of 18. M.P.: 80° C. (gum, K).

Preparation of Compound 72:

Compound 72 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 85 asstarting material (freeze-dried: 72 mg, 45%, yellow powder). M.P.: 80°C. (gum, K).

Preparation Compound 93:

Compound 93 was prepared according to an analogous procedure asdescribed for the synthesis of compound 18, using intermediate 103 asstarting materials (32 mg, 14%, yellow foam). M.P.: 80° C. (gum, K).

Preparation Compound 122:

HCl (3M in cyclopentyl methyl ether) (0.3 mL; 0.9 mmol) was added to asolution of intermediate 118a (163 mg; 0.29 mmol) in 1,4-dioxane (3 mL).The reaction mixture was stirred at 50° C. for 2 h30. Then, more HCl (3Min cyclopentyl methyl ether) (0.3 mL; 0.9 mmol) was added and thereaction mixture was heated at 50° C. for 3 h. Water was added and themixture was slowly basified with NaHCO₃ (solid). The layers wereseparated and the aqueous layer was extracted with DCM (2×) and DCM/MeOH(9/1) (2×). The combined organic layers were dried over MgSO₄, filteredand the solvent was evaporated. The residue (136 mg, orange oil) waspurified by chromatography over silica gel (irregular SiOH; 15-40 μm; 4g; gradient: from 97% DCM, 3% (MeOH/NH₄OH: 95/5) to 85% DCM, 15%(MeOH/NH₄OH: 95/5)). The pure fractions were collected and the solventwas evaporated. The residue (72 mg, pale yellow oil) was purified byreverse phase (X-Bridge-C18 5 μm 30*150 mm; gradient: from 75% (aq.NH₄HCO₃ 0.5%), 25% ACN to 35% (aq. NH₄HCO₃ 0.5%), 65% ACN). The purefractions were collected and the solvent was evaporated to give 37 mg(28%, yellow foam) of compound 122.

Preparation Compound 123:

Compound 123 was prepared according to an analogous procedure asdescribed for the synthesis of compound 122, using intermediate 118b asstarting material (30 mg, 21%, pale yellow foam). M.P.: 80° C. (gum, K).

Preparation Compound 130:

Compound 130 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 122 asstarting material (75 mg, 28%). M.P.: 159° C. (DSC).

Preparation Compound 132:

Compound 132 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 125 asstarting material (120 mg, 36%). M.P.: 80° C. (gum, K).

Preparation Compound 137:

Compound 137 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 129 asstarting material (27 mg, 36%). M.P.: 80° C. (gum, K).

Preparation Compound 138:

Compound 138 was prepared according to an analogous procedure asdescribed for the synthesis of compound 122, using intermediate 132b asstarting material (41 mg, 56%, yellow foam).

Preparation Compound 139:

Compound 139 was prepared according to an analogous procedure asdescribed for the synthesis of compound 122, using intermediate 132c asstarting material (37 mg, 50%, yellow foam).

Preparation Compound 147:

Compound 147 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 135 asstarting material (40 mg, 20%). M.P.: 80° C. (gum, K).

Preparation Compound 152:

Compound 152 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 136 asstarting material (40 mg, 24%). M.P.: 80° C. (gum, K).

Preparation Compound 165:

HCl (4M in 1,4-dioxane) (0.75 mL; 3.01 mmol) was added to a solution ofintermediate 144 (297 mg; 0.52 mmol) in 1,4-dioxane (5 mL). The reactionmixture was stirred at 50° C. for 2 h30. Water was added and the mixturewas slowly basified with 10% aqueous solution of K₂CO₃. The aqueouslayer was extracted with EtOAc. The combined organic layers were driedover MgSO₄, filtered and the solvent was evaporated. The residue (210mg) was purified by chromatography over silica gel (40 g; mobile phase:from 90% DCM, 10% MeOH, 0.5% NH₄OH to 85% DCM, 14% MeOH, 1% NH₄OH). Thepure fractions were collected and the solvent was evaporated to give 130mg (53%) of compound 165. M.P.: 80° C. (gum, K).

Preparation Compound 166:

Compound 166 was prepared according to an analogous procedure asdescribed for the synthesis of compound 165, using intermediate 145 asstarting material (120 mg, 43%). M.P.: 80° C. (gum, K).

Preparation Compound 174:

Compound 174 was prepared according to an analogous procedure asdescribed for the synthesis of compound 165, using intermediate 148b asstarting material (42 mg, 49%). M.P.: 80° C. (gum, K).

Preparation Compound 175:

Compound 175 was prepared according to an analogous procedure asdescribed for the synthesis of compound 165, using intermediate 148c asstarting material (38 mg, 45%). M.P.: 80° C. (gum, K).

Preparation Compound 176:

Compound 176 was prepared according to an analogous procedure asdescribed for the synthesis of compound 165, using intermediate 149 asstarting material (98 mg, 32%). The reaction mixture was stirred at 0°C. for 1 and at rt for 3 h.

Preparation Compound 224:

Compound 224 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 160 asstarting material (crystallized from diethylether; 275 mg, 65%). M.P.:163° C. (DSC).

Preparation of Compound 282, Compound 282a and Compound 282b

Compound 282 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 187 asstarting material. Crystallization from MeOH and Et₂O gave 520 mg ofcompound 282 (54%), MP: 100° C., gum, K). Compound 282 (440 mg) waspurified by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 50%CO₂, 50% EtOH (0.3% iPrNH₂)). The pure fractions were collected and thesolvent was evaporated to give 189 mg of one compound which wascrystallized from Et₂O giving 120 mg (12%) of compound 282a (MP: 100°C., gum, K) and 195 mg of another compound which was crystallized fromEt₂O giving 116 mg (12%) of compound 182b (MP: 100° C., gum, K).

Preparation of Compound 296, Compound 296a and Compound 296b

Compound 296 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 188 asstarting material (725 mg, 87%). Compound 296 (700 mg) was purified bychiral SFC (CHIRALCEL OJ-H 5 μm 250×20 mm; mobile phase: 88.2% CO₂,11.8% MeOH (0.3% iPrNH₂)). The pure fractions were collected and thesolvent was evaporated to give 219 mg of one compound which wascrystallized from pentane giving 180 mg (21%) of compound 296a and 214mg of other compound which was crystallized from pentane giving 161 mg(19%) of compound 296b.

Preparation of Compound 297, Compound 297a and Compound 297b

Compound 297 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 189 asstarting material (465 mg, 73%). Compound 297 was purified by chiral SFC(CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 70% CO₂, 30% iPrOH (0.3%iPrNH₂)). The pure fractions were collected and the solvent wasevaporated to give 179 mg of one compound which was crystallized fromDIPE giving 136 mg (21%) of compound 297a and 136 mg of other compoundwhich was crystallized from DIPE giving 103 mg (16%) of compound 297b.

Preparation of Compound 315a

Compound 315a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 195a asstarting material (84 mg, 44%, MP: 86° C., gum, K).

Preparation of Compound 315b

Compound 315b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 195b asstarting material (96 mg, 38%, M.P.: 90° C. (gum, K).

Preparation of Compound 317

Trifluoroacetic acid (1.028 mL, 13.8 mmol) was added dropwise to asolution of intermediate 205 (0.56 g, 0.92 mmol) in DCM (15 mL) at 0° C.The solution was allowed to warm to room temperature and was stirred atroom temperature overnight. The mixture was poured into water, basifiedwith an aqueous solution of K₂CO₃ 10% and the compound was extractedwith DCM. The organic layer was separated, dried over MgSO₄, filteredand concentrated. The residue (0.39 g) was purified via silica gelchromatography (Stationary phase: irregular bare silica 40 g, Mobilephase: 90% DCM, 10% MeOH (+10% NH₄OH)). The pure fractions werecollected and the solvent was evaporated until dryness and the resultingresidue was crystallized from DIPE. The precipitate was filtered off anddried in vacuo to give 107 mg (23%) of compound 317. M.P: 167° C. (DSC).

Preparation of Compound 318

Compound 318 was prepared according to an analogous procedure asdescribed for the synthesis of compound 317 using intermediate 203 asstarting material (75 mg, 30%).

Preparation of Compound 322a:

Compound 322a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 206a asstarting material (152 mg, 39%, MP: 122° C., K).

Preparation of Compound 322b:

Compound 322b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 206b asstarting material (228 mg, 55%, MP: 80° C., K).

Preparation of Compound 323a:

Compound 323a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 207a asstarting material (246 mg, 62%, MP: 126° C., K).

Preparation of Compound 323b:

Compound 323b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 207b asstarting material (267 mg, 64%, MP: 130° C., K).

Preparation of Compound 324a:

Compound 324a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 208a asstarting material (158 mg, 37%, MP: 60° C., K).

Preparation of Compound 324b:

Compound 324b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 208b asstarting material (100 mg, 23%, MP: 60° C., K).

Preparation of Compound 325a:

Compound 325a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 209a asstarting material (123 mg, 37%, MP: 144° C., K).

Preparation of Compound 325b:

Compound 325b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 209b asstarting material (162 mg, 47%, MP: 138° C., K).

Preparation of Compound 329a:

Compound 329a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 213a asstarting material (175 mg, 50%, MP: 121° C., K).

Preparation of Compound 329b:

Compound 329b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 213b asstarting material (139 mg, 38%, MP: 124° C., K).

Preparation of Compound 335a:

Compound 335a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 215a asstarting material (75 mg, 45%).

Preparation of Compound 335b:

Compound 335b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 315b (69mg, 35%). M.P.: 80° C. (gum, K).

Preparation of Compound 340:

Compound 340 was prepared according to an analogous procedure asdescribed for the synthesis of compound 165, using intermediate 218 asstarting material (133 mg, 52%). M.P.: 180° C., DSC).

Preparation of Compound 344a:

Compound 344a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 220a asstarting material (234 mg, 39%). M.P.: 75° C., gum K).

Preparation of Compound 344b:

Compound 344b were prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 220b asstarting material (258 mg, 44%). M.P.: 75° C., gum K.

Preparation of Compound 345, Compound 345a and Compound 345b

Compound 345 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 221 asstarting material (590 mg; 82%). The separation of the enantiomers from590 mg compound 345 was performed via chiral SFC (Stationary phase:CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% EtOH). Thepure fractions were collected and the solvent was evaporated affording 2fractions which were respectively crystallized from pentane to give 153mg (21%) compound 345a (M.P.: 80° C. (K) and 127 mg (21%) of compound345b (M.P.: 80° C. (K)).

Preparation of Compound 351:

Compound 351 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 222 asstarting material (209 mg g; 29%).

Preparation of Compound 352:

Compound 352 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 223 asstarting material (103 mg g; 32%).

Preparation of Compound 355:

Compound 355 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 224 asstarting material (179 mg, 28%). M.P.: gum (K)).

Preparation of Compound 356a:

Compound 356a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 225a asstarting material (24 mg, 67%).

Preparation of Compound 356b:

Compound 356b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 225b asstarting material (26 mg, 70%).

Preparation of compound 359:

Compound 359 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 226 asstarting material (85 mg, 33%).

Preparation of Compound 362:

Compound 362 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 227 asstarting material (138 mg, 48%).

Preparation of Compound 365:

Compound 365 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 228 asstarting material (110 mg; 66%, M.P: 80° C. gum (K)).

Preparation of Compound 365 a:

Compound 365a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 228a asstarting material (155 mg; 95%, M.P: 80° C. gum (K)).

Preparation of Compound 365b:

Compound 365b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 228b asstarting material (106 mg; 67%, M.P: 80° C. gum (K)).

Preparation of Compound 368:

Compound 368 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 229 asstarting materials. (249 mg, 29%).

Preparation of Compound 370a:

Compound 370a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 230a asstarting material (55 mg, 14%, M.P.: 128° C. (DSC).

Preparation of Compound 370b:

Compound 370b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 270b asstarting material (75 mg, 18%, M.P.: 80° C. (gum, K).

Preparation of Compound 371a:

Compound 371a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 231a asstarting material (174 mg, 43%, M.P.: 114° C., (K)).

Preparation of Compound 371b:

Compound 371b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 271b asstarting material (114 mg, 31%, M.P.: 107° C., (K)).

Preparation of Intermediate 372:

Compound 372 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 232 asstarting material (130 mg; 68%).

Preparation of Compound 374a:

Compound 374a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 233a asstarting material (180 mg, 61%, M.P.: 132° C. (K)).

Preparation of Compound 374b:

Compound 374b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 233b asstarting material (132 mg, 52%, M.P.: 130° C. (K)).

Preparation of Compound 376:

Compound 376 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 234 asstarting material. (26 mg, 4%, M.P.: gum at 130° C., (K))

Preparation of Compound 379a

Compound 379a according to an analogous procedure as described for thesynthesis of compound 17 using intermediate 235a as starting material(41 mg, 31%).

Preparation Compound 379b:

Compound 379b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 235b asstarting material (33 mg, 26%).

Preparation of Compound 380a:

To a solution of intermediate 236a (105 mg; 0.179 mmol) in MeTHF (1.80mL) was added HCl (357 μL; 1.07 mmol, 3M in cyclopentylmethyl ether).The solution was stirred at rt over the weekend then slowly basifiedwith a saturated aqueous solution of NaHCO₃ and DCM was added. Theorganic layer was separated and the aqueous layer was extracted with DCM(2×). The combined organic layers were dried over MgSO₄, filtered offand evaporated. The crude (69 mg) was purified by silica gelchromatography (Irregular SiOH, 15-40 μm, 4 g, Grace, liquid loading(DCM), mobile phase gradient: from DCM 100% to DCM 90%, MeOH/aq. NH₃(95:5) 10%) to give 40 mg of a pale yellow oil which was solubilized inACN (1 mL), extended with water (9 mL) and freeze-dried to give 38 mg(44%) of compound 380a as a yellow fluffy solid.

Preparation of Compound 380b:

Compound 380b was prepared according to an analogous procedure asdescribed for the synthesis of compound 380a using intermediate 236b asstarting material. (26 mg, 27%).

Preparation of Compound 385:

Compound 385 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 240 asstarting material (148 mg, 78%).

Preparation of Compound 386:

Compound 386 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 241 asstarting material (11 mg, 62%)

Preparation of Intermediate 387:

Compound 387 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 242 asstarting material (300 mg; 77%).

Preparation of Compound 389:

Compound 389 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17, using intermediate 243 asstarting material (90 mg, 71%).

Preparation of Compound 390:

Compound 390 was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 244 asstarting material (21 mg, 60%).

Preparation of Compound 122a:

Compound 122a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 118a asstarting material (3.85 g, 34%, MP: 116° C. (DSC)).

Preparation of Compound 123 a:

Compound 123a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 118b asstarting material (73 mg, 9%, MP: 130° C. (DSC)).

Preparation of Compound 404a:

Compound 404a was prepared according to an analogous procedure asdescribed for the synthesis of compound 317 using intermediate 346a asstarting material (99 mg, 66%).

Preparation of Compound 404b:

Compound 404b was prepared according to an analogous procedure asdescribed for the synthesis of compound 317 using intermediate 346b asstarting material (122 mg, 65%).

Preparation of Compound 405 a:

was prepared according to an analogous procedure as described for thesynthesis of compound 317 using intermediate 347a as starting material(110 mg, 70%).

Preparation of Compound 405b:

Compound 405b was prepared according to an analogous procedure asdescribed for the synthesis of compound 317 using intermediate 347b asstarting material (126 mg, 72%).

Preparation of Compound 406a:

Compound 406a was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 348a asstarting material (115 mg, 23%, gums at 80° C. (K)).

Preparation of Compound 406b:

Compound 406b was prepared according to an analogous procedure asdescribed for the synthesis of compound 17 using intermediate 348b asstarting material (213 mg, 47%, gums at 80° C. (K)).

Example B5

Preparation compound 79:

TFA (1.0 mL; 13.07 mmol) was added to a solution of intermediate 86 (180mg; 0.31 mmol) in DCM (2 mL). The reaction mixture was stirred at rt for4 h. The mixture was slowly quenched with a saturated solution ofNaHCO₃. The mixture was then diluted with DCM and water. The layers wereseparated and the aqueous layer was basified with K₂CO₃ (pH 11). Theaqueous layer was extracted with DCM. The combined organic layers weredried over Na₂SO₄, filtered and evaporated under vacuum. The residue(170 mg, greenish oil) was purifed by chromatography over silica gel(irregular SiOH; 15-40 μm; 4 g; gradient: from 99% DCM, 1% (MeOH/NH₄OH:95/5) to 88% DCM, 12% (MeOH/NH₄OH: 95:5)). The pure fractions werecollected and the solvent was evaporated. The resulting residue wasfreeze-dried with water/ACN to give 104 mg (70%, pale yellow fluffysolid) of compound 79.

Preparation of Compound 82:

Compound 82 was prepared according to an analogous procedure asdescribed for the synthesis of compound 79, using intermediate 97 asstarting materials (freeze-dried: 125 mg, 42%).

Example B6

Preparation of compound 81:

HCl (1M in H₂O) (404 μL; 404 μmol) was added to a solution ofintermediate 94 (46 mg; 80.9 μmol) in acetone (1 mL). The reactionmixture was stirred at rt overnight. The mixture was quenched with asaturated aqueous solution of NaHCO₃. The mixture was evaporated invacuum and the residue was taken up in DCM and water. The layers wereseparated and the organic layer was dried over MgSO₄, filtered andevaporated under vacuum. The residue (73 mg, yellow oil) was purified byreverse phase (X-Bridge-C18; 5 μm 30*150 mm; gradient: from 50% (aq.NH₄HCO₃ 0.5%), 50% MeOH to 100% MeOH). The pure fractions were collectedand the solvent was evaporated. The residue was freeze-dried and theproduct (20.5 mg) was purified by achiral SFC (2 ETHYLPYRIDINE; 6 μm150×21.2 mm; mobile phase: 85% CO₂, 15% MeOH). The pure fractions werecollected and the solvent was evaporated. The residue was freeze-driedwith water/ACN (8/2) to give 14 mg (36%) of compound 81.

Example B7

Preparation Compound 19:

In a sealed glass, intermediate 51 (200 mg; 0.46 mmol) and methylamine(2M in THF) (2.28 mL; 4.56 mmol) in THF (4 mL) were stirred at 100° C.overnight. The resulting solution was poured into water and extractedwith EtOAc. The organic layer was dried over MgSO₄, filtered andevaporated until dryness. The residue (245 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 24 g; mobile phase:90% DCM, 10% MeOH, 0.1% MEOH). The pure fractions were collected and thesolvent was evaporated. The residue (79 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 24 g; mobile phase:90% DCM, 10% MeOH, 0.1% NH₄OH). The pure fractions were collected andthe solvent was evaporated to give 41 mg (19%) of compound 19. M.P.: 80°C. (gum, K).

Preparation Compound 94 and Compound 95

Compound 94 and compound 95 were prepared according to an analogousprocedure as described for the synthesis of compound 19, usingintermediate 51 and azetidine as starting materials. The residue (145mg) was purified by chromatography over silica gel (irregular baresilica 12 g; gradient: from 95% DCM, 5% MeOH, 0.1% NH₄OH to 90% DCM, 10%MeOH, 0.1% NH₄OH). The pure fractions were collected and evaporateduntil dryness. The residue (89 mg) was purified by chiral SFC (CHIRALPAKIC 5 μm 250×20 mm; mobile phase: 55% CO₂, 45% EtOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give 25mg of (16%) of compound 94 (M.P.: 80° C., gum, K) and 23 mg (15%) ofcompound 95 (M.P.: 80° C., gum, K).

Example B8

Preparation Compound 20:

A solution of intermediate 52 (300 mg; 0.77 mmol) andN-ethyl-3-fluoroaniline (705 mg; 5.07 mmol) in DMF (3 mL) was heated at60° C. for 2 days in a sealed glassware. The solution was cooled. Then,the mixture was poured into cooled water, basified with K₂CO₃ and theproduct was extracted with EtOAc. The organic layer was washed with H₂O,dried over MgSO₄, filtered and evaporated to dryness. The residue (450mg) was purified by chromatography over silica gel (80 g; mobile phase:50% heptane, 7% MeOH, 43% EtOAc, 0.5% NH₄OH). The pure fractions werecollected and the solvent was evaporated. The residue (168 mg) of waspurified by chromatography over silica gel (irregular bare silica 40 g;mobile phase: 42% heptane, 8% MeOH (+10% NH₄OH), 50% EtOAc). The purefractions were collected and the solvent was evaporated to give 100 mg(26%) of compound 20. M.P.: 80° C. (gum, K).

Preparation Compound 80:

Compound 80 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 87 and3,5-difluoroaniline as starting materials (24 mg, 15%). M.P.: 244° C.(DSC).

Preparation Compound 97:

Compound 97 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 105 and3-fluoro-N-methylaniline as starting materials (405 mg, 22%). M.P.: 146°C. (DSC).

Preparation Compound 99:

Compound 99 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 87 and3-chloro-5-fluoroaniline as starting materials (400 mg, 22%). M.P.: 189°C. (DSC).

Preparation Compound 104:

Compound 104 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 45 and3-fluoroaniline as starting materials (20 mg, 11%). M.P.: 80° C. (gum,K).

Preparation Compound 119:

Compound 119 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3-chloroaniline as starting materials (23 mg, 19%). M.P.: 80° C. (K).

Preparation Compound 120:

Compound 120 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 andm-toluidine as starting materials (28 mg, 25%). M.P.: 80° C. (K).

Preparation Compound 121:

Compound 121 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 andm-anisidine as starting materials (24 mg, 20%). M.P.: 80° C. (K).

Preparation Compound 124:

Compound 124 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3-bromoaniline as starting materials (50 mg, 31%). M.P.: 80° C. (gum,K).

Preparation Compound 125:

Compound 125 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3-ethylaniline as starting materials (50 mg, 34%). M.P.: 80° C. (gum,K).

Preparation Compound 126:

Compound 126 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3,5-dimethylaniline as starting materials (50 mg, 34%). M.P.: 80° C.(gum, K).

Preparation Compound 127 and Compound 128

Compound 127 and compound 128 were prepared according to an analogousprocedure as described for the synthesis of compound 20, usingintermediate 119 and N-methyl-m-toluidine as starting materials. 80 mg(26%) of compound 127; M.P.: 80° C. (gum, K) and 85 mg (27%) of compound128; M.P.: 80° C. (gum, K) were obtained after chiral SFC (Stationaryphase: Chiralpak IA 5 μm 250*20 mm, Mobile phase: 70% CO₂, 30% iPOH(0.3% iPrNH₂)) purification.

Preparation Compound 129:

The solution of intermediate 52 (0.2 g; 0.51 mmol) and intermediate 121(0.74 g; 2.6 mmol) in DMF (5 mL) was heated at 60° C. for 24 h in asealed glassware. The solution was cooled down to rt and poured intocooled water. The mixture was basified with K2CO₃ and the product wasextracted with EtOAc. The organic layer was washed with H₂O, dried overMgSO₄, filtered and evaporated to dryness. The residue (677 mg) wastaken-up with THF (20 mL) and tetrabutylammonium fluoride (3 mL; 10.2mmol) was added. The reaction mixture was stirred at rt overnight. Thesolution was poured into cooled water and the product was extracted withEtOAc. The organic layer was dried over MgSO₄, filtered and evaporatedto dryness. The residue (590 mg) was purified by chromatography oversilica gel (irregular bare silica 40 g; mobile phase: 43% heptane, 7%MeOH (+10% NH₄OH), 50% EtOAc). The pure fractions were collected and thesolvent was evaporated to give 39 mg (14%) of compound 129. M.P.: 80° C.(K).

Preparation Compound 131:

Compound 131 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3-aminobenzonitrile as starting materials (49 mg, 34%). M.P.: 80° C.(K).

Preparation Compound 133:

Compound 133 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3,5-dichloroaniline as starting materials (25 mg, 16%). M.P.: 80° C.(gum, K).

Preparation Compound 134:

Compound 134 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3,5-dimethoxyaniline as starting materials (26 mg, 17%). M.P.: 80° C.(gum, K).

Preparation Compound 135:

Compound 135 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 119 andsodium thiophenolate as starting materials (148 mg, 58%, pale yellowsolid). M.P.: 144° C. (DSC).

Preparation Compound 140 and Compound 141

Compound 140 and compound 141 were prepared according to an analogousprocedure as described for the synthesis of compound 20, usingintermediate 119 and 3-chloro-N-methylaniline as starting materials. 69mg (21%) of compound 140; M.P.: 80° C. (gum, K) and 69 mg (21%) ofcompound 141; M.P.: 80° C. (gum, K) were obtained after chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% MeOH (0.3% iPrNH₂)) purification.

Preparation Compound 146:

Compound 146 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 52 and3-chloro-5-fluoroaniline as starting materials (29 mg, 19%). M.P.: 80°C. (gum, K).

Preparation Compound 150:

Compound 150 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 119 andaniline as starting materials (75 mg, 26%). M.P.: 110° C. (K).

Preparation Compound 153:

Compound 153 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 139 and3,5-difluoroaniline as starting materials (90 mg, 23%, pale yellowfoam). M.P.: 90° C. (gum, K).

Preparation Compound 155:

Compound 155 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 119 and3-aminobenzonitrile as starting materials (57 mg, 18%). M.P.: 186° C.(DSC).

Preparation Compound 158 and Compound 159

3-Difluoroaniline (1.36 g; 10.55 mmol) was added to a solution ofintermediate 20 ((730 mg; 2.11 mmol) in DMF (19 mL) under N₂. Thesolution was stirred at 60° C. for 7 days in a sealed tube. The solutionwas cooled, poured out into cooled water, basified with K₂CO₃. EtOAc wasadded. The product was extracted with EtOAc and the organic layer wasconcentrated. Et₂O was added and a precipitate was filtered off. Theprecipitate was purified via silica gel chromatography (SiO₂: 80 g,Mobile phase: 45% heptane 5% MeOH 50% EtOAc 0.5% NH₄OH). The purefractions were collected and evaporated until dryness to give 450 mg ofan impure fraction of the racemic compound. This residue was purifiedvia silica gel chromatography (SiO₂: 80 g, Mobile phase: 67% heptane 3%MeOH 30% EtOAc 0.5% NH₄OH). The pure fractions were collected andevaporated until dryness to give of 322 mg (35%) of the racemiccompound. Separation of the enantiomers was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 85% CO₂,15% MeOH (0.3% iPrNH₂)). The pure fractions were collected andevaporated until dryness to give 134 mg (14%) of compound 158 and 120 mg(13%) of compound 159.

Preparation Compound 167:

Compound 167 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 145 and3,5-difluoroaniline as starting materials (15 mg, 6%). M.P.: 80° C.(gum, K). The reaction mixture was stirred at 50° C. for 36 h.

Preparation of Compound 260:

A mixture of intermediate 87 (1 g; 2.17 mmol), 2,5-difluoroaniline (1.1mL; 10.84 mmol) in DMF (10 mL) was stirred at 50° C. for 48 h in asealed tube. The solution was poured into cooled water. EtOAc was addedand the mixture was filtered through a pad of Celite®. The product wasextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand evaporated to dryness. The residue (1.2 g) was crystallized fromEt₂O and dried to give 0.32 g (34%, yellow solid) of compound 260.

Preparation of Compound 264:

Compound 264 was prepared according to an analogous procedure asdescribed for the synthesis of compound 262 (alternative pathway), usingintermediate 87 and 3-chloro-5-fluoroaniline as starting materials (400mg, 42%). The reaction mixture was stirred at 50° C. for 48 h. M.P.:189° C. (DSC).

Preparation of Compound 266:

Compound 266 was prepared according to an analogous procedure asdescribed for the synthesis of compound 260, using intermediate 105 and3,4,5-trifluoroaniline as starting materials (2.72 g, 64%, M.P.: 220° C.(K)). The reaction mixture was stirred at 60° C. for 4 days.

Preparation of Compound 269:

Compound 269 was prepared according to an analogous procedure asdescribed for the synthesis of compound 262, using intermediate 105 and3,5-difluoro-4-(trifluoromethyl)aniline as starting materials(crystallized from Et₂O; 865 mg; 34%).

Preparation of Compound 293:

Compound 293 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 105 and4-methyl-3-fluoroaniline as starting material (4.12 g, 65%). M.P.: 186°C., K).

Preparation of Compound 304:

Compound 304 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20 using intermediate 194 find3,5-difluoroaniline as starting materials (10 mg, 5%).

Example B9

Preparation Compound 156 and Compound 157

Thiomorpholine 1,1-dioxide (86 mg; 0.63 mmol) and K2CO₃ (117 mg; 0.85mmol) were added to a mixture of intermediate 140 (177 mg; 0.42 mmol) inACN (4 mL). The reaction mixture was stirred at 80° C. overnight. Themixture was cooling down to rt, combined with another batch coming froma reaction performed on 63 mg of intermediate 140 and poured into water.The organic layer was extracted with EtOAc, washed with brine, driedover MgSO₄, filtered and evaporated until dryness. The residue (420 mg)was purified by chromatography over silica gel (40 g; mobile phase: from100% DCM to 98% DCM, 2% MeOH). The pure fractions were collected and thesolvent was evaporated until dryness. The residue (racemic, 220 mg) waspurified by chiral SFC (CHIRALPAK IC 5 μm; 250×20 mm; mobile phase: 60%CO₂, 40% EtOH). The pure fractions were collected and the solvent wasevaporated to give 101 mg (34%) of compound 156 and 98 mg (33%) ofcompound 157.

Preparation Compound 160:

Compound 160 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and2-thia-6-aza-spiro[3.3]heptane 2,2-dioxide as starting materials (98 mg,28%). M.P.: 229° C. (DSC).

Preparation Compound 161:

Compound 161 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and2-thia-6-aza-spiro[3.3]heptane 2,2-dioxide as starting materials (109mg, 31%). M.P.: 228° C. (DSC).

Preparation Compound 162:

Compound 162 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and2,2,2-trifluoroethylamine as starting materials (60 mg, 25%). M.P.: 80°C. (gum, K).

Preparation Compound 163:

2.07 HCl 1.40 H₂O Compound 163 was prepared according to an analogousprocedure as described for the synthesis of compound 156, usingintermediate 143 and 2,2,2-trifluoroethylamine as starting materials.After the purification, the residue (140 mg) was dissolved in ACN,converted into hydrochloric acid salt ([HCl/iPrOH 5M]; 3 eq./V=0.17mL]). The salt was filtered to give 150 mg (51%) of compound 163 (2.07HCl 1.40 H₂O). M.P.: 239° C. (DSC).

Preparation Compound 164:

Compound 164 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 140 and2,2-difluoroethylamine as starting materials (76 mg, 23%). M.P.: 116° C.(DSC).

Preparation Compound 168:

Compound 168 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 140 andmorpholine as starting materials (121 mg, 31%). M.P.: 165° C. (DSC).

Preparation Compound 173:

Compound 173 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and2-(methylsulfonyl)-ethanamine hydrochloride as starting materials (65mg, 21%). M.P.: 80° C. (gum, K).

Preparation Compound 192:

Compound 192 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and2,8-Dioxa-5-azaspiro[3.5]nonane oxalate salt as starting materials (34mg, 11%). M.P.: 229° C. (DSC).

Preparation Compound 193:

Compound 193 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and(R)-(2-Hydroxymethyl)morpholine HCl as starting materials (105 mg, 35%).M.P.: 80° C. (gum, K).

Preparation Compound 194:

Compound 194 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and(S)-(2-Hydroxymethyl)morpholine HCl as starting materials (152 mg, 51%).M.P.: 80° C. (gum, K).

Preparation Compound 195:

Compound 195 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and2,8-Dioxa-5-azaspiro[3.5]nonane oxalate salt as starting materials (110mg, 43%). M.P.: 228° C. (DSC).

Preparation Compound 196:

Compound 196 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and(S)-(2-Hydroxymethyl)morpholine HCl as starting materials (freeze-dried:158 mg, 63%). M.P.: 80° C. (gum, K).

Preparation Compound 197:

Compound 197 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and(R)-(2-Hydroxymethyl)morpholine HCl as starting materials (freeze-dried:170 mg, 68%). M.P.: 80° C. (gum, K).

Preparation Compound 205:

Compound 205 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and(3R,4R)-3,4-Dimethoxypyrrolidine hydrochloride as starting materials (85mg, 35%). M.P.: 80° C. (gum, K).

Preparation Compound 206:

Compound 206 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 andcis-2,6-dimethylmorpholine as starting materials (97 mg, 41%). M.P.: 80°C. (gum, K).

Preparation Compound 207:

Compound 207 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and(3R,4R)-3,4-Dimethoxypyrrolidine hydrochloride as starting materials(freeze-dried: 94 mg, 35%). M.P.: 80° C. (gum, K).

Preparation Compound 208:

Compound 208 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 andcis-2,6-dimethylmorpholine as starting materials (133 mg, 52%). M.P.:80° C. (K).

Preparation Compound 210:

Compound 210 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 142 and4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine hydrochloride as startingmaterials (91 mg, 45%). M.P.: 80° C. (K).

Preparation Compound 222:

Compound 222 was prepared according to an analogous procedure asdescribed for the synthesis of compound 156, using intermediate 143 and4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine hydrochloride as startingmaterials (17 mg, 7%). M.P.: 163° C. (DSC).

Example B10

Preparation Compound 21 and Compound 22

A solution of intermediate 58 (76 mg; 0.15 mmol) and p-toluenesulfonicacid monohydrate (6 mg; 29 μmol) in MeOH (6.38 mL) was heated at 50° C.for 3 days. The resulting solution was evaporated under reducedpressure. The residue was dissolved in EtOAc (10 mL) and washed with asaturated aqueous solution of NaHCO₃ (5 mL). The aqueous layer wasextracted with EtOAc (2×10 mL). The combined organic layers were driedover MgSO₄, filtered and evaporated under reduced pressure. The residuewas combined with another batch from 127 mg of intermediate 58 andpurified by chromatography over silica gel (irregular SiOH; 15-40 μm; 24g; gradient: from 100% EtOAc to 85% EtOAc, 15% MeOH (+5% NH₄OH)). Thepure fractions were collected and the solvent was evaporated. Theresidue (105 mg, brown powder) was combined with another batch comingfrom a reaction performed on 165 mg of intermediate 58 and purified byreverse phase (X-Bridge-C18 5 μm 30*150 mm; gradient: from 65% aq.NH₄HCO₃ 0.5%, 35% ACN to 25% aq. NH₄HCO₃ 0.5%, 75% ACN). The purefractions were collected and the solvent was evaporated. The residue(158 mg) was purified by chiral SFC (Lux cellulose 4; 5 μm 250*21.2 mm;mobile phase: 75% CO₂, 25% MeOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give 59 mg (19%, yellowpowder) of compound 21 (M.P.: 184° C. (DSC)) and 54 mg (17%, yellowpowder) of compound 22 (M.P.: 183° C. (DSC)).

Example B11

Preparation of Compound 177:

TFA (0.8 mL; 10.27 mmol) was added at 10° C. to a solution ofintermediate 150 (0.18 g; 0.34 mmol) in MeOH (20 mL). The reactionmixture was stirred at rt for 24 h. The solution was cooled and themixture was poured into cooled water, basified with K2CO₃ and theproduct was extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and evaporated to dryness. The residue (130 mg) waspurified by chromatography over silica gel (irregular bare silica 10 g;mobile phase: 97% DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions werecollected and the solvent was evaporated. The residue (73 mg) wasfreeze-dried with ACN/water 20/80 to give 69 mg (45%, yellow powder) ofcompound 177. M.P.: 80° C. (gum, K)).

Preparation of Compound 178:

Compound 178 was prepared according to an analogous procedure asdescribed for the synthesis of compound 177, using intermediate 151 asstarting materials (freeze-dried: 122 mg, 61%, yellow powder of compound178; M.P.: 80° C. (gum, K).

Example B12

Preparation of Compound 229:

TBAF (0.69 mL; 0.69 mmol) was added to a mixture of intermediate 163(350 mg; 0.63 mmol) in THF (9 mL) and the reaction mixture was stirredat rt for 2 h. The mixture was concentrated and the residue was purifiedby chromatography over silica gel (SiOH 15 μm; 25 g mobile phase: 100%DCM to 90% DCM, 10% MeOH, 1% NH₄OH). The pure fractions were collectedand the solvent was evaporated. The residue was crystallized withdiisopropylether/ACN (drops) under sonicated. The precipitate wasfiltered and dried to give 195 mg (63%) of compound 229.

Preparation of Compound 230:

Compound 230 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229, using intermediate 165 asstarting material (186 mg, 79%, M.P.: 218° C. (DSC)).

Preparation of Compound 231:

Compound 231 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229, using intermediate 164 asstarting material (102 mg, 42%)

Preparation of Compound 232:

Compound 232 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229, using intermediate 166 asstarting material (197 mg, 82%, M.P.: 181° C. (DSC)).

Preparation of Compound 244:

TBAF (0.37 mL, 1 M, 0.37 mmol) was added to a mixture of intermediate174 (200 mg, 0.34 mmol) in THF (4.9 mL) and the reaction mixture wasstirred at rt for 2 hours. The mixture was concentrated and the residue(420 mg) was purified by chromatography over silica gel (SiOH 15 μm, 25g mobile phase: gradient from 98% DCM 2% MeOH 0.2% NH₄OH to 90% DCM 10%MeOH 0.1% NH₄OH). The pure fractions were collected. The solvent wasevaporated and crystallized from DIPE/ACN to give 78 mg (48%) ofcompound 244

Preparation of Compound 245:

Compound 245 was prepared according to an analogous procedure asdescribed for the synthesis of compound 244, using intermediate 175 asstarting material, (87 mg; 41%) of compound 245.

Preparation of Compound 276:

Tetrabutylammoniumfluoride (0.6 mL, 1 M in THF, 0.6 mmol) was added to amixture of intermediate 180 (300 mg, 0.542 mmol) in THF (8 mL) and thereaction mixture was stirred at rt for 2 hours. The mixture wasconcentrated and the residue was purified by silica gel chromatography(SiO₂ 15 μm, 25 g, mobile phase: 98% DCM 2% MeOH 0.2% NH₄OH to 90% DCM10% MeOH 1.1% NH₄OH). The pure fractions were concentrated and theresulting residue was crystallized from DIPE/ACN (drop) undersonication. The precipitate was filtered to give 155 mg (65%) ofcompound 276 (M.P.: 194° C. (DSC)).

Preparation of Compound 336:

Compound 336 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229, using intermediate 216 asstarting material (155 mg, 65%). M.P.: 195° C. (DSC).

Preparation of Compound 343:

Compound 343 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229, using intermediate 219 asstarting material (955 mg, 57%).

Preparation of Compound 391, Compound 391a and Compound 391b

Compound 391 was prepared according to an analogous procedure asdescribed for the synthesis of compound 229 using intermediate 245 asstarting material (390 mg; 70%). The separation of the enantiomers wasperformed by chiral SFC (CHIRALPAK DIACEL OJ 250×20 mm; mobile phase:CO₂, EtOH-iPrOH (50-50)+0.4% iPrNH₂). The pure fractions were collectedand the solvent was evaporated to give, after freeze-drying, 26 mg (5%)of compound 391a and 29 mg (5%) of compound 391b.

Example B13

Preparation of Compound 56:

In a microwave vial, 3,5-difluorophenol (31 mg; 0.24 mmol) and PPh₃ (62mg; 0.24 mmol) were added to a solution of intermediate 76 (61 mg; 0.16mmol) in THF (1.6 mL). Then, di-tert-butyl azodicarboxylate (55 mg; 0.24mmol) was added and the mixture was stirred at rt for 18 h. Then, more3,5-difluorophenol (31 mg; 0.24 mmol), PPh₃ (62 mg; 0.24 mmol) anddi-tert-butyl azodicarboxylate (55 mg; 0.24 mmol) were addedsuccessively and the mixture was stirred at 40° C. for 18 h. The mixturewas combined with another batch coming from a reaction performed on 20mg of intermediate 76. The mixture was evaporated under vacuum andtaken-up in DCM. The organic layer was washed with a saturated solutionof NaHCO₃, dried over MgSO₄, filtered and evaporated in vacuum. Theresidue (400 mg, yellow oil) was purified by chromatography over silicagel (irregular SiOH; 15-40 μm; 10 g; gradient: from 100% DCM to 96.5%DCM, 3.5% MeOH). The pure fractions were collected and the solvent wasevaporated. The residue (160 mg, yellow solid) was purified by achiralSFC (CYANO 6 μm 150×21.2 mm; mobile phase: 92% CO₂, 8% MeOH). The purefractions were collected and the solvent was evaporated. The residue wasfreeze-dried with water-ACN (80/20) to give 32 mg (31%, white fluffysolid) of 56. M.P.: 55° C. (DSC).

Preparation of Compound 68:

Compound 68 was prepared according to an analogous procedure asdescribed for the synthesis of compound 56, using intermediate 17 and3-fluorophenol as starting materials (freeze-dried: 58 mg, 23%, yellowfluffy solid). M.P.: 49° C. (DSC).

Preparation Compound 73 and Compound 74

Compound 73 and compound 74 were prepared according to an analogousprocedure as described for the synthesis of compound 56, usingintermediate 17 and 2,3-difluorophenol as starting materials. 63 mg(24%, yellow fluffy solid) of compound 73 and 64 mg (24%, pale fluffysolid) of compound 74 were obtained after chiral SFC (Stationary phase:CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% EtOH)purification.

Preparation of Compound 78:

Compound 78 was prepared according to an analogous procedure asdescribed for the synthesis of compound 56, using intermediate 17 and2-bromo-5-fluorophenol as starting materials (freeze-dried: 24 mg, 3%,yellow fluffy solid). M.P.: 235° C. (DSC).

Preparation of Compound 151:

In a sealed glassware, phenol (41 mg; 0.43 mmol) andcyanomethylenetributylphosphorane (0.15 mL; 0.58 mmol) were added to asolution of intermediate 17 (100 mg; 0.29 mmol) in toluene (3 mL). Thereaction mixture was stirred at 60° C. overnight. The mixture wasevaporated under vacuum to dryness. The residue (350 mg, brown oil) waspurified by chromatography over silica gel (40 g; mobile phase: 40%heptane, 10% MeOH, 50% EtOAc, 0.5% NH₄OH). The pure fractions werecollected and the solvent was evaporated until dryness. The residue (120mg) was purified by chromatography over silica gel (40 g; mobile phase:45% heptane, 5% MeOH, 50% EtOAc, 0.5% NH₄OH). The pure fractions werecollected and the solvent was evaporated to give 17 mg (14%) of compound151. M.P.: 80° C. (gum, K).

Preparation of Compound 209:

Compound 209 was prepared according to an analogous procedure asdescribed for the synthesis of compound 151, using intermediate 15 and3,4-difluorophenol as starting materials (crystallized fromdiethylether: 1.4 g, 52%). M.P.: 183° C. (DSC).

Preparation of Compound 247:

3,5-difluorophenol (480 mg; 3.69 mmol), di-tert-butyl azodicarboxylate(849 mg; 3.69 mmol) and PPh₃ (967 mg; 3.69 mmol) were added to asolution of intermediate 15 (1 g; 2.46 mmol) in THF (24 mL). Thereaction mixture was stirred at rt overnight. Then, additional3,5-difluorophenol (480 mg; 3.69 mmol), di-tert-butyl azodicarboxylate(849 mg; 3.69 mmol) and PPh₃ (967 mg; 3.69 mmol) were added and themixture was stirred at 60° C. for 4 h. The mixture was filtered througha pad of Celite® and the filtrate was evaporated under vacuum. Theresidue was triturated in Et₂O, filtered and the filtrate was evaporatedunder vacuum. The resulting residue (2.5 g, orange oil) was purifiedchromatography over silica gel (regular SiOH 30 μm; 80 g; mobile phase:from 100% DCM to 70% DCM, 30% EtOAc). The pure fractions were collectedand the solvent was evaporated to give 1.36 g (84%, yellow oil) ofcompound 247.

Preparation of Compound 256:

Compound 256 was prepared according to an analogous procedure asdescribed for the synthesis of compound 247, using intermediate 15 and3-fluorophenol as starting materials (1.44 g, 46%, yellow oil).

Alternative Pathway:

Compound 256 was prepared according to an analogous procedure asdescribed for the synthesis of compound 277, using intermediate 15 and3-fluorophenol as starting materials (1.57 g, 62%, yellow powder).

Preparation of Compound 277:

3,5-difluorophenol (228 mg; 1.76 mmol) andcyanomethylenetributylphosphorane (614 μL; 2.34 mmol) were successivelyadded to a solution of intermediate 56 (396 mg; 1.17 mmol) in toluene(11.9 mL). The reaction mixture was heated at 60° C. overnight. Theresulting solution was concentrated under reduced pressure. The residuewas purified by chromatography over silica gel (irregular SiOH; 15-40μm; 24 g; gradient: from 90% heptane, 9% EtOAc, 1% MeOH to 60% heptane,36% EtOAc, 4% MeOH). The pure fractions were collected and the solventwas evaporated 330 mg (63%, pale orange powder) of compound 277.

Preparation of Compound 310:

Compound 310 was prepared according to an analogous procedure asdescribed for the synthesis of compound 151 using intermediate 15 and4-chloro-3-fluorophenol as starting materials (1.75 g, 100%).

Preparation of Compound 377,

Compound 377 was prepared according to an analogous procedure asdescribed for the synthesis of compound 151, using intermediate 15 and3,4,5-Trifluorophenol as starting material (2.13 g, 62%).

Preparation of Compound 403, Compound 403a and Compound 403b

Compound 403 was prepared according to an analogous procedure asdescribed for the synthesis of compound 247, using intermediate 17 and3,5-difluorophenol as starting materials (233 mg, 99%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% iPrOH). The pure fractions were mixed and the solvent was evaporatedto afford respectively, after freeze-drying, 32 mg (15%) of compound403a (MP: 53° C., DSC) and 31 mg (14%) of compound 403b (MP: 54° C.,DSC).

Example B14

Preparation of Compound 96:

Hydrazine hydrate (132 mg; 1.35 mmol) was added to a solution ofintermediate 104 (750 mg; 1.35 mmol) in MeOH (20 mL). The solution washeated at reflux (70° C.) for 20 h. The solution was poured into cooledwater and the organic layer was extracted with DCM, dried over MgSO₄,filtered and evaporated until dryness. The residue (425 mg) was purifiedby chromatography over silica gel (irregular 15-40 μm; 24 g; mobilephase: 90% DCM, 10% MeOH, 0.1% NH₄OH). The pure fractions were collectedand evaporated. The residue (97 mg) was purified by chromatography oversilica gel (irregular 15-40 μm; 24 g; mobile phase: 90% DCM, 10% MeOH,0.1% NH₄OH). The pure fractions were collected and evaporated untildryness to give 45 mg (8%) of compound 96. M.P.: 80° C. (gum, K).

Example B15

Preparation of Compound 233:

Compound 233 was prepared according to an analogous procedure asdescribed for the synthesis of compound 262, using intermediate 105 and3,4-difluoroaniline as starting material (7 g; 52%) M.P.: 210° C. (K)).

Preparation of Compound 235:

3,5-difluoroaniline (16.4 g; 0.13 mmol) was added to a solution ofintermediate 105 (8.5 g; 0.025 mol) in DMF (200 mL) under N₂. Thesolution was stirred at 60° C. for 48 hours in a sealed tube. Thesolution was cooled, poured out into cooled water, basified with K₂CO₃and EtOAc was added. The mixture was extracted with EtOAc and theorganic layer was concentrated. The residue was taken up Et₂O and aprecipitate was filtered and dried given 7.2 g (66%) of compound 235.

Example B16

Preparation Compound 250:

MnO₂ (2.08 g; 24 mmol) was added portionwise to a solution of compound10 (1.7 g; 3.99 mmol) in DCM (77 mL). The reaction mixture was stirredat rt overnight. The mixture was filtered through a pad of Celite® andthe filtrate was evaporated to give 1.65 g (97%) of compound 250. M.P:120° C. (K).

Preparation of Compound 271:

Manganese oxide (782 mg; 8.99 mmol) was added portionwise to a solutionof compound 84 (600 mg; 1.5 mmol) in DCM (30 mL). The mixture wasstirred at rt overnight. The mixture was filtered through a pad ofCelite® and evaporated until dryness. Then, the residue was taken-upwith diisopropylether to give 500 mg (83%) of compound 271. In case thiscompound was used in a conversion to another compound, it was used assuch without further purification.

Example B17

Preparation of Compound 262:

Thioglycolic acid (234 μL; 3.36 mmol) was added to a solution ofintermediate 107 ((1 g; 1.68 mmol) and1,8-diazabicyclo(5.4.0)undec-7-ene (1 mL; 6.72 mmol) in ACN (16 mL). Thesolution was stirred at rt for 1 h. Then DCM and 10% aqueous solution ofNa₂CO₃ were added. The organic layer was separated and the aqueous layerwas extracted with DCM (2×). The combined organic layers were dried overMgSO₄, filtered and evaporated under vacuum. The residue was purified bychromatography over silica gel (Irregular SiOH 15-40 μm; 30 g; gradient:from 100% DCM to 95% DCM, 5% MeOH/NH₄OH (95/5)). The pure fractions werecollected and the solvent was evaporated to give 2 fractions of compound262 respectively 242 mg (35%, yellow solid) and 382 mg (55%, pale brownsolid). Global yield: 90%

Alternative Pathway:

3-fluoroaniline (1.75 mL; 18.17 mmol) was added to a solution ofintermediate 105 (1.05 g; 3.13 mmol) in DMF (12 mL) under N₂. Thesolution was stirred at 60° C. for 48 h in a sealed tube. The solutionwas cooling down to rt, then poured into cooled water and basified withK₂CO₃. EtOAc was added. The organic layer was extracted, washed withH₂O, dried over MgSO₄ and evaporated to dryness. The residue (3.4 g) wastaken-up with DCM, MeOH and E_(t2)O. A precipitate was filtered, washedwith a mixture of MeOH and Et₂O and dried to give 0.66 g (51%) ofcompound 262. M.P.: 222° C. (DSC).

Preparation of Compound 262a and Compound 262b

Compound 262a and 262b were obtained after separation of compound 262 bySFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 70%CO₂, 25% iPrOH (0.3% iPrNH₂)). After concentration of the solvent, eachfraction was crystallized from Et₂O yielding, after filtration, 747 mg(37%) of compound 262a (M.P: 199.7° C. (DSC)) and 775 mg (39%) ofcompound 262b, (M.P: 199.5° C. (DSC)).

Alternative Preparation of Compound 262a:

Intermediate 182 was dissolved in acetonitrile (10 volumes) and1,8-diazabicyclo[5.4.0]undec-7-ene (4.0 eq.) and 2-mercaptoacetic acid(2.0 eq.) were added. The reaction mixture was stirred for 16 hours atroom temperature. After concentration to about 2 volumes, water (7volumes) was added. Compound 262a was isolated and dried in 92% yield(e.e.: 83.3%).

To improve the e.e., the solid obtained as described above was slurriedtwice in EtOAc according to the scheme below:

Example B18

Preparation of Compound 278:

A mixture of intermediate 5 (200 mg; 0.55 mmol), 3,5-difluorobenzylamine(117.5 mg; 0.82 mmol) and cesium carbonate (535.2 mg; 1.64 mmol) intoluene (3 mL) was purged with nitrogen. Then, BrettPhos PrecatalystFirst Gen (4.4 mg; 0.0055 mmol) was added. The tube was sealed and thereaction was heated at 100° C. for 72 hours. Then, the reaction wascooled down to rt, poured onto water and filtered through a pad ofCelite®. The aqueous layer was extracted with EtOAc. The organic layerwas dried over MgSO₄, filtered and concentrated.

The residue (420 mg) was purified by silica gel chromatography(irregular SiOH, 30 g, mobile phase: 97% DCM 3% MeOH 0.1% NH₄OH). Thefractions containing the product were mixed and concentrated to afford225 mg of an intermediate fraction which was taken up with Et₂O. Theresulting precipitate was filtered, washed with Et₂O twice then dried toafford 80 mg (34%) of compound 278. M.P. 158° C. (K).

Preparation of Compound 288

Compound 288 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 163, using intermediate 3aas starting material and 3,5-difluorobenzylamine. (7.67 g; 66%)

Preparation of Compound 305

In a schlenk round flask, a mixture of intermediate 3a (10 g, 28.394mmol), 3-Fluoro-2-methylbenzylamine 4.428 mL, 34.073 mmol) and cesiumcarbonate (18.503 g, 56.788 mmol) in tert-amyl alcohol (130 mL) wasdegazed with N₂. 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl(0.662 g, 1.42 mmol) and BrettPhos Precatalyst First Gen (1.134 g, 1.42mmol) were added, The reaction mixture was purged with N₂ and heated at100° C. for 18 h. The reaction mixture was poured into water and EtOAc.The organic layer was separated, washed with brine, dried over MgSO₄ andevaporated till dryness. The residue was taken up with DIPE. Then, thesolid was filtered to give (7.8 g, 67%) of compound 305.

Preparation of Compound 383

Compound 383 was prepared according to an analogous procedure asdescribed for the synthesis of compound 305 using intermediate 237 and3-fluoro-2-methylbenzylamine as starting materials (204 mg, 43%, M.P:172° C. (DSC)).

Preparation of Compound 395, Compound 395a and Compound 395b

Compound 395 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1 using intermediate 5 and2-(3,5-difluorophenyl)pyrrolidine as starting materials (133 mg, 42%,M.P: 80° C., gum (K)).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% iPrOH (0.3% iPrNH₂)). The pure fractions were mixed and the solventwas evaporated to afford, after freeze-drying, respectively 47 mg (15%)of compound 395a (MP: 90° C., gum, K) and 45 mg (14%) of compound 395b(MP: 102° C., K).

Preparation of Compound 396 (Mixture of 4 Unseparable Diastereoisomers)

Compound 396 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1 using intermediate 5 and2-(3,5-difluorophenyl)pyrrolidine as starting materials (89 mg, 50%).

Preparation of Compound 397, Compound 397a and Compound 397b

Compound 397 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1 using intermediate 5 and2-(4-fluorophenyl)azetidine as starting materials (450 mg, 75%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 73% CO₂,27% iPrOH). The pure fractions were mixed and the solvent was evaporatedto afford, respectively, 60 mg of compound 397a (MP: 80° C., gum, K) and92 mg of compound 397b (MP: 80° C., gum, K).

Preparation of Compound 398

Compound 398 was prepared according to an analogous procedure asdescribed for the synthesis of compound 1 using intermediate 28a and(2R)-2-(3,5-difluorophenyl)pyrrolidine as starting materials (32 mg,28%).

Preparation of Compound 399

Compound 399 was prepared according to an analogous procedure asdescribed for the synthesis of compound 278 using intermediate 5 and2-Methyl-3-(trifluoromethyl)benzylamine as starting materials (55 mg,21%, MP: 202° C. (K)).

Preparation of Compound 400

Compound 400 was prepared according to an analogous procedure asdescribed for the synthesis of compound 278 using intermediate 5 and4-fluorobenzylamine as starting materials (92 mg, 41%, MP: 80° C., gum(K)).

Preparation of Compound 401

Compound 401 was prepared according to an analogous procedure asdescribed for the synthesis of compound 278 using intermediate 5 and(S)-4-Fluoro-α-methylbenzylamine as starting materials (6 mg, 3%, MP:80° C., gum (K)).

Preparation of Compound 402

Compound 402 was prepared according to an analogous procedure asdescribed for the synthesis of compound 278 using intermediate 5 and(RS)-1-(3,5-Difluorophenyl)ethylamine as starting materials (25 mg, 5%,MP: 80° C., gum (K)).

Example B19

Preparation of Compound 301

In a sealed tube, 3-fluoro-1-methylaniline (60.4 μL, 0.536 mmol) wasadded to a solution of intermediate 191 (177 mg, 0.536 mmol) andglycolaldehyde dimer (32.2 mg, 0.268 mmol) in hexafluoroisopropanol(1.07 mL). The mixture was stirred at room temperature for 14 days. Theresulting solution was concentrated under reduced pressure. The crudeproduct was purified by reverse phase (Stationary phase: X-Bridge-C18 5μm 30*150 mm, Mobile phase: Gradient from 85% aq. NH₄HCO₃ 0.2%, 15% ACNto 45% aq. NH₄HCO₃ 0.2%, 55% ACN) to give compound 301 (18.6 mg, 8%, MP:315° C., DSC) as a yellow powder

Example B20

Preparation of Compound 326

To a solution of intermediate 212 (949 mg, 2.32 mmol) in DCM (23 mL) wasadded sodium triacetoxybororohydride (1.48 g, 6.97 mmol). The mixturewas stirred at rt overnight then DCM and water were added. The organiclayer was separated, dried over MgSO₄, filtered off and evaporated invacuo to give 1.52 g of compound 326 as a yellow solid directly used inthe next step without any further purification.

Preparation of Compound 330:

Compound 330 was prepared according to an analogous procedure asdescribed for the synthesis of compound 326 using intermediate 214 asstarting material (504 mg, used without purification in the next step).

Example B21 Preparation of Compound 339, Compound 339a and Compound 339b

A solution of 3-fluorophenylacetone (110 mg, 0.723 mmol) andN-tosylhydrazine (135 mg, 0.723 mmol) in 1,4-dioxane (2.89 mL) wasstirred at 80° C. for 1.5 h. K2CO₃ (150 mg, 1.08 mmol) and intermediate191 (386 mg, 1.08 mmol) were successively added and the reaction mixturewas heated to 110° C. for 3 days. The resulting solution was cooled downto room temperature and concentrated under reduced pressure. The residuewas taken up in a saturated aqueous NaHCO₃ solution (10 mL) andextracted with DCM (3×20 mL). The combined organic layers were washedwith a saturated aqueous NaHCO₃ solution (2×20 mL) and brine (20 mL),dried over MgSO₄, filtered and concentrated under reduced pressure.

The residue was purified by silica gel chromatography (irregular SiOH,15-40 μm, 24 g, mobile phase gradient: from DCM 100% to DCM 80%, MeOH20%) to give of an impure fraction of compound 339 as an orange foamThis residue was purified by reverse phase (Stationary phase:X-Bridge-C18 5 μm 30*150 mm, Mobile phase: Gradient from 65% aq. NH₄HCO₃0.2%, 35% ACN to 25% aq. NH₄HCO₃ 0.2%, 75% ACN) to give 105 mg (34%) ofcompound 339 as a yellow powder. M: 117° C. (DSC).

Compound 339 was purified by chiral SFC (Stationary phase: CHIRALPAKAD-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% iPrOH) to give 2fractions which were triturated in a mixture of pentane/Et₂O (5:1, 6mL). The precipitates were filtered on glass frit to give 16.1 mg (5%)of compound 339a_as a light yellow powder (M.P: 131° C. (DSC) and 16.7mg, (5%) of compound 339b as a light yellow powder (M.P: 128° C. (DSC).

C. Conversion to Final Compounds Conversion C1

Preparation of Compound 5, Compound 6 and Compound 53

DIPEA (0.42 mL; 2.41 mmol) and HBTU (365 mg; 0.963 mmol) were added to asolution of compound 248 (400 mg; 0.96 mmol) in dry DMF (9.5 mL). Thereaction mixture was stirred at rt for 30 min. Then, dimethylamine (2Min THF) (0.72 mL; 1.44 mmol) was added and the reaction mixture wasstirred at rt overnight. The mixture was evaporated in vacuum and theresidue was taken-up with EtOAc. The organic layer was washed with asaturated aqueous solution of NaHCO₃, brine (2×), dried over MgSO₄,filtered and evaporated under vacuum. The residue (520 mg, beige foam)was purified by chromatography over silica gel (irregular SiOH 15-40 μm;25 g; mobile phase: from 100% DCM to 40% DCM, 60% EtOAc). The purefractions were collected and the solvent was evaporated to give 393 mg(92%) of compound 53. The residue (393 mg) was purified by chiral SFC(CHIRALPAK AD-H; 5 μm 250×20 mm; mobile phase: 75% CO₂, 25% EtOH). Thepure fractions were collected and the solvent was evaporated to give twofractions which were freeze-dried with water-ACN to give 186 mg (44%,pale yellow fluffy solid) of compound 5 and 182 mg (43%, pale yellowfluffy solid) of compound 6.

Preparation of Compound 33: A

Compound 33 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 andazetidine hydrochloride as starting materials (83 mg, 38%). M.P.: 280°C. (DSC).

Preparation of Compound 34:

Compound 34 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and2-thia-6-azaspiro[3.3]heptane,2,2-dioxide,2,2,2-trifluoroacetate asstarting materials (68 mg, 48%). M.P.: 160° C. (K).

Preparation of Compound 37:

Compound 37 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 253 andazetidine hydrochloride as starting materials (61 mg, 43%). M.P.: 276°C. (DSC).

Preparation of Compound 38:

Compound 38 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 andthiomorpholine 1,1-dioxide as starting materials (67 mg, 48%). M.P.:146° C. (K).

Preparation of Compound 39:

Under N2, at rt, 2,6-Dimethylpiperazine (44 mg; 0.38 mmol) was added toa solution of compound 251 (110 mg; 0.25 mmol), HBTU (142 mg; 0.38mmol), and DIPEA (0.13 mL; 0.75 mmol) in DMF (3 mL). The solution wasstirred at rt for 64 hours. The solution was poured into cooled water.The product was extracted with DCM and the organic layer was dried overMgSO₄, filtered and evaporated to dryness. The residue (180 mg) waspurified by silica gel chromatography (Spherical bare silica 5 μm150×30.0 mm, Mobile phase: Gradient from 98% DCM, 2% MeOH (+10% NH₄OH)to 88% DCM, 12% MeOH (+10% NH₄OH)). The fractions were collected andevaporated until dryness and freeze-dried with CH₃CN/water to afford 81mg (60%) of compound 39. M.P.: 80° C. (gummed, K)).

Preparation of Compound 40:

Compound 40 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 andmethylamine (2M in THF) as starting materials (freeze-dried: 51 mg, 35%,yellow powder). M.P.: 80° C. (gum, K).

Preparation of Compound 43:

Compound 43 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 253 andthiomorpholine 1,1-dioxide as starting materials (freeze-dried: 46 mg,45%). M.P.: 80° C. (gum, K).

Preparation of Compound 46:

Compound 46 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 253 and2,6-dimethylpiperazine as starting materials (freeze-dried: 30 mg, 31%).M.P.: 80° C. (gum, K).

Preparation of Compound 47:

Compound 47 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and2-oaxa-6 aza-spiro(3,3)heptane as starting materials (freeze-dried: 32mg, 25%). M.P.: 80° C. (gum, K).

Preparation of Compound 50:

Compound 50 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and2-(methylamino)ethanol as starting materials (freeze-dried: 35 mg, 28%).M.P.: 80° C. (gum, K).

Preparation of Compound 51:

Compound 51 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 andN,O-dimethylhydroxylamine hydrochloride as starting materials(freeze-dried: 14 mg, 32%, yellow powder). M.P.: 80° C. (gum, K).

Preparation of Compound 59, compound 60 and compound 61

Compound 59, compound 60 and compound 61 were prepared according to ananalogous procedure as described for the synthesis of compound 5, usingcompound 248 and 2-(methylamino)ethanol as starting material (388 mg,85%, pale yellow solid of compound 59. Separation of the enantiomers bychiral SFC (Stationary phase: CHIRALPAK AD-IT 5 μm 250×20 mm, Mobilephase: 80% CO₂, 20% iPrOH (0.3% iPrNH₂)) of 355 mg of racemic compound59 gave respectively 145 mg (32%, yellow fluffy solid) of compound 60and 125 mg (27%, pale fluffy solid) of compound 61.

Preparation of Compound 63:

Compound 63 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 and(azetidin-3-yl)methanol as starting materials (freeze-dried: 29 mg,25%). M.P.: 100° C. (gum, K).

Preparation of Compound 64:

Compound 64 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 and(S)-(+)-2-pyrrolidinemethanol as starting materials (freeze-dried: 51mg, 43%). M.P.: 80° C. (gum, K).

Preparation of Compound 65:

Compound 65 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 and3-hydroxyazetidine hydrochloride as starting materials (freeze-dried: 51mg, 45%). M.P.: 80° C. (gum, K).

Preparation of Compound 66:

Compound 66 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 and3-amino-1-propanol as starting materials (freeze-dried: 46 mg, 41%).M.P.: 80° C. (gum, K).

Preparation of Compound 69:

Compound 69 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 and1-isopropylpiperazine as starting materials (freeze-dried: 44 mg, 35%,white powder). M.P.: 80° C. (gum, K).

Preparation of Compound 70:

Compound 70 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and(2R)-aminopropan-1-ol as starting materials (freeze-dried: 77 mg, 57%,white powder). M.P.: 80° C. (gum, K).

Preparation of Compound 71:

Compound 71 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 62 andethanolamine as starting materials (freeze-dried: 79 mg, 36%, yellowpowder). M.P.: 80° C. (gum, K).

Preparation of Compound 75:

Compound 75 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and4-aminopiperidine as starting material (freeze-dried: 14 mg, 12%). M.P.:80° C. (gum, K).

Preparation of Compound 86 and Compound 87

Compound 86 and compound 87 was prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound257a and (S)-(+)-2-(pyrrolidinemethanol) as starting material. Theresidue (680 mg, orange oil) was purified by chromatography over silicagel (regular SiOH; 30 μm; 40 g; gradient: from 99.5% DCM, 0.5% MeOH to95% DCM, 5% MeOH). The pure fractions were collected and the solvent wasevaporated. The residue (340 mg, pale yellow foam) was purified byachiral SFC (CHIRALPAK AD-H; 5 μm; 250×20 mm; mobile phase: 65% CO₂, 35%EtOH). The pure fractions were collected and the solvent was evaporatedto give two fractions which were solubilized in DCM, evaporated anddried under vacuum (50° C., 24 h) to give 115 mg (25%, pale yellow foam)of compound 86 (M.P.: 76° C., DSC) and 125 mg (28%, pale yellow foam) ofcompound 87 (M.P.: 74° C., DSC)

Preparation of Compound 90, Compound 91 and Compound 92

Compound 90, compound 91 and compound 92 was prepared according to ananalogous procedure as described for the synthesis of compound 5, usingcompound 257a and 1-ethylpiperazine as starting material. The residue(420 mg, brown oil) was purified by chromatography over silica(irregular SiOH; 15-40 μm; 12 g; gradient: from 98% DCM, 2% MeOH to 94%DCM, 6% MeOH). The pure fractions were collected and the solvent wasevaporated to give 2 fractions of compound 90 respectively:

-   -   Fraction A: 72 mg of compound 90. 30 mg of this fraction were        solubilized in MeCN and washed with pentane. The MeCN layer was        evaporated under vacuo and the solid was triturated in Et₂O to        give, after filtration, 21 mg of compound 90 (6%, off-white        foam).    -   Fraction B: 270 mg of compound 90 which were combined with the        residual 42 mg of fraction A. The resulting residue (312 mg) was        purified by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm; mobile        phase: 70% CO₂, 30% EtOH (0.3% iPrNH₂)). The pure fractions were        collected and the solvent was evaporated to give two fractions        which were separately co-evaporated in DCM (2×) and dried under        reduced pressure (16 h, 50° C.) to give respectively 92 mg (27%,        pale yellow foam) of compound 91 and 101 mg (30%, pale yellow        foam) of compound 92.

Preparation of Compound 105:

Compound 105 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 98 andmorpholine as starting materials (96 mg, 52%). M.P.: 161° C. (DSC).

Preparation of Compound 113 and Compound 114

Compound 113 and compound 114 were prepared according to an analogousprocedure as described for the synthesis of compound 5, usingintermediate 117 and 1-ethylpiperazine as starting material (74 mg, 40%,pale yellow solid of compound 113; M.P.: 307° C. (DSC) and 74 mg, 40%,pale yellow solid of compound 114; M.P.: 303° C. (DSC) were obtainedafter chiral SFC (Stationary phase: Chiralpak AS-H 5 μm 250*20 mm,Mobile phase: 60% C02, 40% MeOH (0.3% iPrNH₂)) purification).

Preparation of Compound 115 and Compound 116

Compound 115 and compound 116 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound263 and L-prolinol as starting materials (67 mg, 33%, pale yellow solidof compound 115; M.P.: 327° C. (DSC) and 77 mg, 37%, pale yellow solidof compound 116; M.P.: 332° C. (DSC) were obtained after chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 80% CO₂,20% EtOH (0.3% iPrNH₂)) purification).

Preparation of Compound 117 and Compound 118

To a solution of compound 263 (120.0 mg; 303 μmol), HBTU (230 mg; 0.605mmol), and DIPEA (313 μL; 1.82 mmol) in DMF (3 mL) was added2-aminoethanol (36.3 μL; 0.605 mmol). The solution was stirred at roomtemperature for 1 h. Then, water and DCM were added. The organic layerwas separated, dried over MgSO₄, filtered off, evaporated under vacuumand purified by silica gel chromatography (Irregular SiOH 15-40 μm, 24g, liquid injection (DCM), mobile phase gradient: from DCM 100% to DCM90%, iPrOH/aq NH₃ (95:5) 10%) to give 144 mg (yellow foam) of racemiccompound. The separation of the enantiomers was performed by chiral SFC(CHIRALCEL OJ-H 5 μm 250×20 mm; Mobile phase: 70% CO₂, 30% EtOH (0.3%iPrNH₂)) The pure fractions were collected and the solvent wasevaporated to give 63 mg (41%, pale yellow solid) of compound 117 and 67mg (43%) of compound 118 (M.P.: 237° C., DSC).

Alternative Preparation of Compound 117:

To a solution of compound 274 (94 mg, 0.237 mmol), HBTU (0.179 g, 0.474mmol), and DIPEA (0.245 mL, 1.423 mmol) in DMF (3 mL) was added2-aminoethanol (0.028 mL, 0.474 mmol) under N₂. The solution was stirredat rt for 15 h. The solution was cooled and the mixture was poured intocooled water, the product was extracted with EtOAc. The organic layerwas washed with H₂O, separated, dried over MgSO₄, filtered andevaporated to dryness. The residue 120 mg was purified by chromatographyover silica gel (Irregular SiOH 15-40 μm 24 g: gradient from 98% DCM, 2%MeOH to 90% DCM, 10% MeOH, 0.1% NH₄OH). The pure fractions werecollected and the solvent was evaporated until dryness to give 32 g(31%) of compound 117 (ee=91.8%)

Preparation of Compound 117:

Compound 274 was coupled with ethanolamine (2.0 eq.) in DMF (3 volumes)using DIPEA (6.0 eq.) and HBTU(N,N,N′,N′-tetramethyl-<9-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate) (2.0 eq) at room temperature. After completereaction the mixture was diluted with EtOAc, washed with 5% NaHCO₃ andconcentrated to a residue. The solid was then slurried in THF (10volumes) to improve the purity and the e.e. The procedure was executedrespectively on 20 and 95 g scale of compound 274 and gave compound 117in an average yield of 77% (e.e: 99.4%). The batches were then combinedand for removing the THF, the resulting solid was dissolved in ethanol.The solvent was evaporated to a residue twice, and the residing solidwas then dried at 50° C. under reduced pressure overnight to obtain 90 gof compound 174a as a hemi-ethanolate solvate (e.e: 99.4%).

Preparation of Compound 142:

Compound 142 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 251 and1-ethylpiperazine as starting materials (107 mg, 80%). M.P.: 80° C.(gum, K).

Preparation of Compound 143:

Compound 143 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83a and1-ethylpiperazine as starting materials (136 mg, 74%). M.P.: 80° C.(gum, K).

Preparation of Compound 144:

Compound 144 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83a and1-methylpiperazine as starting materials (156 mg, 87%). M.P.: 80° C.(gum, K).

Preparation of Compound 145:

Compound 145 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83a and2-(methylamino)ethanol as starting materials (134 mg, 79%). M.P.: 80° C.(gum, K).

Preparation of Compound 148:

Compound 148 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83a and2-thia-6-aza-spiro[3.3]heptane 2,2 dioxide as starting materials (124mg, 47%).

Preparation of Compound 149:

Compound 149 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83a and2,2′-oxybis(ethylamine) as starting materials (48 mg, 26%). M.P.: 80° C.(gum, K).

Preparation of Compound 169:

Compound 169 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 83 a and2-amino-2-methyl-1-propanol as starting materials (89 mg, 25%). M.P.:217° C. (DSC).

Preparation of Compound 171 and Compound 172

Compound 171 and compound 172 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound83a and 1-(2,2,2-trifluoroethyl)piperazine as starting materials (104mg, 38%, compound 171 (M.P.: 125° C. (gum, K)) and 100 mg, 37%, compound172 (M.P.: 130° C. (gum, K) were obtained after chiral SFC (Stationaryphase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 85% CO₂, 15% MeOH(0.3% iPrNH₂)) purification).

Preparation of Compound 180, Compound 181 and Compound 182

N,N,N′-trimethylethylenediamine (185 μL; 1.45 mmol) was added to asolution of compound 83a (300 mg; 0.72 mmol), HBTU (549 mg; 1.45 mmol)and DIPEA (0.75 mL; 4.34 mmol) in Me-THF (10 mL). The reaction mixturewas stirred at rt for 16 h. The mixture was poured into water, extractedwith EtOAc and washed with brine (2×). The organic layer was dried overMgSO₄, filtered and the solvent was evaporated. The residue (520 mg) waspurified by column chromatography over silica gel (40 g; mobile phase:from 100% DCM to 97% DCM, 3% MeOH, 0.3% NH₄OH). The pure fractions werecollected and the solvent was evaporated to give 295 mg (82%) ofcompound 180. M.P.: 148° C. (K). Compound 180 was purified by chiral SFC(AS-H 5 μm 250*20 mm; mobile phase: 80% CO₂, 20% EtOH). The purefractions were collected and the solvent was evaporated to give twofractions which were crystallized in diethylether, filtered and driedunder vacuum to give 38 mg (11%) of compound 181 (M.P.: 134° C., DSC)and 60 mg (16%) of compound 182 (M.P.: 134° C., DSC).

Preparation of Compound 183, Compound 184 and Compound 185

To a solution of compound 83a (300 mg; 0.72 mol), HBTU (550 mg; 1.45mmol) and DIPEA (0.75 mL; 4.34 mmol) in DMF (6 mL) was addedN,N-dimethylethylenediamine (0.16 mL; 1.45 mmol) and the mixture wasstirred at rt for 16 h. The mixture was poured into water and extractedwith EtOAc. The organic layer was washed with brines (×2), dried overMgSO₄, filtrated and evaporated until dryness. The residue was purifiedvia silica gel chromatography (Stationary phase: 40 g, Mobile phasefrom: 100% DCM to 97% DCM 3% MeOH 0.3% NH₄OH. The pure fractions werecollected and evaporated until dryness to give 290 mg (83%) of compound183. Separation of the enantiomers was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 85% CO₂,15% MeOH (0.3% iPrNH₂)). The pure fractions were collected andevaporated until dryness. Each fractions were crystallized form Et₂O togive 70 mg (20%) of compound 184 (M.P.: 157° C. (DSC)), and 58 mg (20%)of compound 185 (M.P.: 152° C. (DSC)).

Preparation of Compound 188 and Compound 189

Compound 188 and compound 189 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound83a and 2-aminoethanol as starting materials (82 mg, 25%, compound 188(M.P.: 80° C. (gum, K)) and 94 mg, 87%, compound 189 (M.P.: 80° C. (gum,K) were obtained after chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 μm250×20 mm, Mobile phase: 75% CO₂, 25% EtOH (0.3% iPrNH₂)) purification).

Preparation of Compound 198, Compound 199 and Compound 200

Compounds 198, 199 and 200 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound39 and 2-aminoethanol as starting materials. 130 mg (24%) of compound198 were obtained after crystallization in a mixture of Et₂O/DCM. M.P.:171° C. (DSC). Compound 198 was purified by chiral SFC (CHIRALCEL OJ-H 5μm 250×20 mm; mobile phase: 90% CO₂, 10% MeOH). The pure fractions werecollected and the solvent was evaporated. Each residue was crystallizedfrom DCM/diethylether. Each precipitate was filtered and dried undervacuum to give 68 mg (12%) of compound 199 (M.P.: 140° C., K) and 57 mg(10%) of compound 200 (M.P.: 115° C., gum, K).

Preparation of Compound 201 and Compound 202

Compound 201 and compound 202 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound83a and (2R)-(−)-1-aminopropan-2-ol as starting materials. 253 mg (22%)of compound 201 (M.P.: 70° C., DSC) and 276 mg (24%) of compound 202were obtained after chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 μm250×20 mm, Mobile phase: 83% CO₂, 17% MeOH (0.3% iPrNH₂)) purification.

Preparation of Compound 203 and Compound 204

Compound 203 and compound 204 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound83a and 2-methoxyethylamine as starting material (after purification toseparate the enantiomers from 280 mg of racemic compound andcrystallization from diethylether; 28 mg (8%) of compound 203 (M.P.:118° C., DSC) and 76 mg (22%) of compound 204 (M.P.: 80° C., gum, K).

Preparation of Compound 211 and Compound 212

A solution of compound 83a (1 g; 2.41 mmol), HBTU (1.37 g; 3.62 mmol)and DIPEA (1.25 mL; 7.24 mmol) in DMF (25 mL) was stirred at rt for 15min. Then, N-isopropylethylenediamine (0.46 mL; 3.62 mmol) was added andthe solution was stirred at rt for 15 h. The product was poured in icewater and extracted with EtOAc. The organic layer was washed with brine(×2), dried over MgSO₄, filtered and evaporated until dryness. Theresidue was purified by silica gel chromatography (Stationary phase:irregular SiOH 15-40 μm 300 g MERCK, Mobile phase: 0.1% NH₄OH, 95% DCM,0.5% MeOH). The fractions containing the product were mixed andconcentrated to afford 720 mg of the racemate.

This racemate was purified by chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 90% CO₂, 10% MeOH (0.3% iPrNH₂)). Thefractions containing the products were mixed and concentrated to afford320 mg of fraction A and 315 mg of fraction B.

Fraction A was crystallized from a mixture of DCM/Et₂O. The precipitatewas filtered off and dried under vacuum to give 280 mg (23%) of compound211 (M.P.: 206° C. (DSC)).

Fraction B was crystallized from a mixture of DCM/Et₂O. The precipitatewas filtered off and dried under vacuum to give 250 mg (21%) of compound212 (M.P.: 204° C. (DSC)).

Preparation of Compound 213 and Compound 214

Compound 213 and compound 214 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound170 and 2-aminoethanol as starting materials. 117 mg (27%) of compound213 (M.P.: 80° C., gum, K) and 136 mg (31%) of compound 214 (M.P.: 80°C., gum, K) were obtained after chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 80% CO₂, 20% MeOH (0.3% iPrNH₂))purification.

Preparation of Compound 217:

Compound 217 (undefined mixture of 4 diastereoisomers) was preparedaccording to an analogous procedure as described for the synthesis ofcompound 5, using compound 83a and 3-(trifluoroacetamido)pyrrolidine asstarting materials (crystallized from diisopropylether; 120 mg, 29%).

Preparation of Compound 218, Compound 219 and Compound 220

1,1′-Carbonyldiimidazole (324 mg; 2.0 mmol) was added to a solution ofcompound 83a (690 mg; 1.67 mmol) in Me-THF (14 mL) and the mixture washeated at reflux for 2 h. The mixture was cooled down to rt andcyclopropanesulphonamide (202 mg; 1.67 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (370 μL; 2.50 mmol) were added. Themixture was stirred at rt overnight. The mixture was poured into water.The organic layer was extracted with DCM, separated, dried over MgSO₄,filtered and evaporated. The residue was purified by chromatography oversilica gel (Irregular SiOH 15-40 μm; 40 g; gradient: from 100% DCM to90% DCM, 10% MeOH, 0.1% MEOH). The pure fractions were collected and thesolvent was evaporated until dryness to give 970 mg of compound 218. Apart (106 mg) was crystallized from DIPE. The precipitate was filteredoff and dried under vacuum to give 59 mg of compound 218.

The rest of the compound 218 was purified by chiral SFC (CHIRALCEL OJ-H5 μm; 250×20 mm; mobile phase: 60% CO₂, 40% MeOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give twofractions which were crystallized from diisopropylether. Eachprecipitate was filtered off and dried under vacuum to give 312 mg (33%)of compound 219 and 248 mg (29%) of compound 220.

Preparation of Compound 223:

Compound 223 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 159 and2-aminoethanol as starting materials (crystallized from DCM; 195 mg,60%). M.P.: 200° C. (DSC).

Preparation of Compound 226, Compound 227 and Compound 228

Compounds 226, 227 and 228 were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound263 and N-isopropylethylenediamine as starting materials. Aftercrystallization from diethylether 192 mg (49%) of compound wereobtained. M.P.: 158° C. (DSC). Compound 226 was purified by chiral SFC(CHIRALPAK AD-H 5 μm; 250×20 mm; mobile phase: 60% CO₂, 40% EtOH). Thepure fractions were collected and the solvent was evaporated. Eachresidue was freeze-dried with ACN/water (20/80) to give 74 mg (19%,yellow powder) of compound 227 (M.P.: 80° C., gum, K) and 76 mg (20%,yellow powder) of compound 228 (M.P.: 80° C., gum, K).

Preparation of Compound 237, Compound 237a, Compound 237b, Compound 237cand Compound 237d

Compound 237 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 and2-Trifluoromethylpiperazine (R/S: 80/20) as starting materials. Theresidue (700 mg) was purified by chromatography over silica gel(irregular 15-40 μm; mobile phase: 97% DCM, 3% MeOH (+10% NH₄OH)). Thepure fractions were collected and the solvent was evaporated. Theresidue (500 mg) was crystallized from Heptane and Et₂O. The precipitatewas filtered and dried to give (0.45 g, 67% of compound 237 (M.P: 105°C. (Kofler). Compound 237 was further purified by chiral SFC (CHIRALCELOJ-H; 5 μm 250×20 mm; mobile phase: 80% CO₂, 20% MeOH (0.3% iPrNH₂)).The pure fractions were collected and the solvent was evaporated to give2 fractions of diastereoisomers. The first fraction of diastereoisomerswas purified by chiral SFC (CHIRALPAK AD-H, 5 μ*250*20 mm; mobile phase85% CO₂, 15% EtOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give 2 fractions. The first one (122 mg)was crystallized from Et₂O to give after filtration 94 mg of compound237b (M.P: 120° C. (Kofler)) and the second one (38 mg) was freeze-driedwith water-ACN to give 33 mg (5%) of compound 237d (M.P.: 80° C.(Kofler). The second fraction was purified by chiral SFC (CHIRALPAKAD-H, 5 μ*250*20 mm; mobile phase 82% CO₂, 18% EtOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give 2fractions. The first one (120 mg) was crystallized from Et₂O to giveafter filtration 66 mg (10%) of compound 237a (M.P.:120° C. (Kofler) andthe second one (43 mg) was freeze-dried with water-ACN to give 40 mg(6%) of compound 237c (M.P.:80° C. (Kofler)).

Preparation of Compound 238:

Compound 238 (was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 and1-(2,2,2-trifluroethyl)-3-azetidiamine as starting materials(Heptane/Et₂O, 350 mg, 45%). M.P: 110° C. (gum, K).

Preparation of Compound 243, Compound 243a and Compound 243b

Compound 243 (was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 andsulfamide as starting materials. The residue (480 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 40 g, mobile phase:100% DCM). The pure fractions were collected; The solvent was evaporatedand a part of product was crystallized from DIPE. The precipitate wasfiltered and dried to give (41 mg) of compound 243. The residue waspurified by chiral SFC (CHIRALPAK AD-H, 5 μ*250*20 mm; mobile phase 60%CO₂, 40% MeOH). The pure fractions were collected and the solvent wasevaporated to give 2 fractions which were taken up DCM and evaporated togive 98 mg (20%) of compound 243a (M.P.:160° C. (Kofler)) and 96 mg(20%) of compound 243b (M.P: 200° C. (Kofler))

Preparation of Compound 246, Compound 246a and Compound 246b

Compound 246 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 and(2S)-1-amino-2-propanol as starting materials. The residue (580 mg) waspurified by chromatography over silica gel (irregular 15-40 μm; 40 g,mobile phase: gradient from 100% DCM to 97% DCM 3% MeOH 0.3% NH₄OH). Thepure fractions were collected and the solvent was evaporated to give 345mg of compound 246. This compound was purified by chiral SFC (CHIRALCELOJ-H, 5 μ*250*20 mm; mobile phase 75% CO₂, 25% MeOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give 2fractions which were crystallized from Et₂O and dried to give 123 mg(36%) of compound 246a and 118 mg (34%) of compound 246b (M.P: 75° C.(DSC)).

Preparation of Compound 272, Compound 272a and Compound 272b

Compound 272 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 andD-proline methylester hydrochloride as starting materials The residuewas purified by chromatography over silica gel (irregular bare silica 40g; mobile phase: gradient from 100% DCM to 0.1% MEOH, 90% DCM, 10%MeOH). The pure fractions were collected and the solvent was evaporatedto give 250 mg (78%) of compound 272. Compound 272 was purified bychiral SFC (CHIRALCEL OJ-H; 5 μm 250×20 mm; mobile phase: 75% CO₂, 25%MeOH). The pure fractions were collected and the solvent was evaporatedto give respectively 87 mg (27%) of compound 272a and 86 mg (27%) ofcompound 272b.

Preparation of Compound 273, Compound 273a and Compound 273b

Compound 273 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 236 andL-proline methylester hydrochloride as starting material The residue waspurified by chromatography over silica gel (irregular bare silica 40 g;mobile phase: gradient from 100% DCM to 0.1% NH₄OH, 90% DCM, 10% MeOH).The pure fractions were collected and the solvent was evaporated to give320 mg of compound 273. Compound 273 was purified by chiral SFC(CHIRALCEL OJ-H; 5 μm 250×20 mm; mobile phase: 80% CO₂, 20% MeOH). Thepure fractions were collected and the solvent was evaporated to giverespectively 105 mg (33%) of compound 273a and 96 mg (32%) of compound273b.

Preparation of Compound 279, Compound 279a and Compound 279b

Compound 279 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 234 and2-aminoethanol as starting materials (570 mg, 65%). M.P=77° C. DSC.

Compound 179 was purified by chiral SFC (Stationary phase: CHIRALPAKAD-H 5 μm 250×20 mm, Mobile phase: 55% C02, 45% EtOH (0.3% iPrNH2)) togive 150 mg of each enantiomers which were freeze-dried with a mixtureof ACN and water (1/3) giving 90 mg (10%) of compound 279a (M.P.: 80°C., gum, K) and 100 mg (11%) of compound 279b (M.P.: 80° C., gum, K).

Preparation of Compound 280, Compound 280a and Compound 280b

Compound 280 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 234 and3-Amino-1-propanol as starting materials (330 mg, 72%, M.P: 164° C.,DSC).

Compound 280 was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm;mobile phase: 60% CO₂, 40% MeOH). The pure fractions were collected andthe solvent was evaporated to give 140 mg of one compound which werefreeze-dried with a mixture of ACN and water (1/3) giving 105 mg (10%)of compound 280a: (MP: 80° C., gum, K) and 135 mg of another compoundwhich were freeze-dried with a mixture of ACN and water (1/3) giving 120mg (26%) of compound 280b (MP: 80° C., gum, K).

Preparation of Compound 281, Compound 281a and Compound 281b

Compound 281 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 andN,N-dimethylethylenediamine as starting materials (570 mg, 100%, M.P=80°C., K)

Compound 281 was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm;mobile phase: 60% CO₂, 40% MeOH). The pure fractions were collected andthe solvent was evaporated to give 253 mg of one compound which wascrystallized from pentane giving 136 mg (23%) of compound 281a (MP: 102°C., K) and 234 mg of another compound which was crystallized frompentane giving 164 mg (28%) of compound 281b (MP: 80° C., gum, K).

Preparation of Compound 283a and Compound 283b

Compound 283a and compound 283b were prepared according to an analogousprocedure as described for the synthesis of compound 5, using compound170 and N-isopropylethylenediamine as starting materials giving 290 mg(97%) of a racemic intermediate compound which was purified by chiralSFC (CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 60% CO₂, 40% EtOH(0.3% iPrNH₂)). The pure fractions were collected and the solvent wasevaporated to give 102 mg of one compound which was crystallized fromEt₂O giving 63 mg (21%) of compound 283a: (MP: 173° C., DSC) and 105 mgof other compound which was crystallized from Et₂O giving 60 mg (20%) ofcompound 283b: (MP: 170° C., DSC).

Preparation of Compound 284a and Compound 284b

Compound 284a and compound 284b were prepared according to an analogousprocedure as described for the synthesis of compound 5 using compound170 and (2R)-(−)-1-aminopropan-2-ol as starting materials giving 745 mg(84%) of aracemic compound, which was purified by chiral SFC (CHIRALCELOJ-H 5 μm 250×20 mm; mobile phase: 83% CO₂, 17% EtOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give 323mg of one compound which was crystallized from pentane giving 190 mg(21%) of compound 284a (MP: 113° C., K) and 368 mg of another compoundwhich was crystallized from pentane giving 240 mg (27%) of compound 284b(MP: 112° C., K).

Preparation of Compound 286, Compound 286a and Compound 286b

Compound 286 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 285 andN-isopropylethylenediamine, as starting materials (645 mg, 67%, MP: 85°C., gum, K).

Compound 286 (598 mg) was purified by chiral SFC (CHIRALPAK AD-H 5 μm250×30 mm; mobile phase: 65% CO₂, 35% EtOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 262 mgof one compound which was crystallized from Et₂O giving 187 mg (19%) ofcompound 286a (MP: 85° C., gum, K) and 231 mg of other compound whichwas crystallized from Et₂O giving 220 mg (23%) of compound 286b (MP: 85°C., gum, K).

Preparation of Compound 287, Compound 287a and Compound 287b

Compound 287 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 234 and(6S)-1,4-diazabicyclo[4,3,0]nonane as starting materials (1.03 g, 82%,M.P=80° C., gum, K).

Compound 287 (980 mg) was purified by chiral SFC (CHIRALPAK AD-H 5 μm250×20 mm; mobile phase: 70% CO₂, 30% MeOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 274 mg(22%) of one compound which was crystallized from DIPE giving 255 mg(20%) of compound 287a (MP: 90° C., K) and 185 mg of other compoundwhich was crystallized from Et₂O giving 130 mg (10%) of compound 287b(MP: 95° C., gum, K).

Preparation of Compound 292, Compound 292a and Compound 292b

Compound 292 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 170 and1-amino-2-methylpropan-2-ol as starting materials (650 mg, 93%, MP: 80°C., gum, K).

Compound 292 (650 mg) was purified by chiral SFC (CHIRALCEL OJ-H 5 μm250×20 mm; mobile phase: 80% CO₂, 20% MeOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 310 mgof one compound which was crystallized from pentane and Et₂O giving 186mg (27%) of compound 292a (MP: 110° C., gum, K) and 305 mg of othercompound which was crystallized from pentane and Et₂O giving 190 mg(27%) of compound 292b (MP: 110° C., gum, K).

Preparation of Compound 295, Compound 295a and Compound 295b:

Compound 295 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 294 and ethanolamine as starting materials (700 mg, 79%, MP: 80° C., gum, (K)).

Compound 295 was purified by chiral SFC (CHIRALPAK IC-H 5 μm 250×30 mm;mobile phase: 60% CO₂, 40% iPrOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give 276 mg of one compoundwhich was crystallized from pentane giving 244 mg (28%) of compound 295a(MP: 120° C., gum, K) and 291 mg of other compound which wascrystallized from pentane giving 225 mg (25%) of compound 295b (MP: 120°C., gum, K).

Preparation of Compound 298a and Compound 298b

Compound 298a and compound 298b were prepared according to an analogousprocedure as described for the synthesis of compound 5 using compound285 and (R)-(+)-3-(Dimethylamino)pyrrolidine as starting materials. Theseparation of the enantiomers from 360 mg of racemic compound wasperformed by chiral SFC (CHIRALPAK AD-IT 5 μm 250×30 mm; mobile phase:60% CO₂, 40% EtOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give one compound which was crystallizedfrom pentane and Et₂O giving 74 mg (20%) of compound 298a (MP: 100° C.,gum, K) and the other compound which was crystallized from pentane andEt₂O giving 45 mg (12%) of compound 298b (MP: 100° C., gum, K).

Preparation of Compound 299a and Compound 299b

Compound 299a and compound 299b were prepared according to an analogousprocedure as described for the synthesis of compound 5 using compound285 and N,N-dimethylethylenediamine as starting materials. Theseparation of the enantiomers from 440 mg of racemic compound wasperformed by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase:78% CO₂, 22% EtOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give one compound which was crystallizedfrom DCM and Et₂O giving 98 mg (17%) of compound 299a (MP: 100° C., gum,K) and the other compound which was crystallized from DCM and Et₂Ogiving 86 mg (15%) of compound 299b (MP: 100° C., gum, K).

Preparation of Compound 300, Compound 300a and Compound 300b

Compound 300 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 234 and(R)-(−)-3-pyrrolidinol as starting materials. (723 mg, 88%).

Compound 300 was purified by chiral SFC (CHIRALPAK DIACEL AD 250×30 mm;mobile phase: CO₂, iPrOH (0.4% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give one compound which wascrystallized from Et₂O giving 152 mg (19%) of compound 300a (MP: 140°C., K) and another compound which was crystallized from Et₂O giving 130mg (16%) of compound 300b (MP: 135° C., K).

Preparation of Compound 302, Compound 302a and Compound 302b

Compound 302 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 234 and(S)-3-hydroxypiperidine hydrochloride as starting materials. (637 mg,100%, MP:80° C., K). Compound 302 was purified by chiral SFC (CHIRALPAKAS-H 5 μm 250×20 mm; mobile phase: 65% CO₂, 35% EtOH (0.3% iPrNH₂)). Thepure fractions were collected and the solvent was evaporated to give 376mg of one compound which was crystallized from pentane giving 90 mg(15%) of compound 302a (MP: 135° C., K) and 245 mg of another compoundwhich was crystallized from pentane giving 245 mg (41%) of compound 302b(MP: 135° C., K).

Preparation of Compound 308:

Compound 308 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 307 find2-Thia-6-azaspiro[3.3]heptane, 2,2-dioxide as starting materials (156mg, 59%, MP: 195° C., DSC).

Preparation of Compound 309, Compound 309a and Compound 309b

Compound 309 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 170 andN,N-dimethylethylenediamine as starting materials (610 mg, 100%).Compound 309 was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250×30 mm;mobile phase: 70% CO₂, 30% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give 208 mg of one compoundwhich was crystallized from Et2O giving 192 mg (33%) of compound 309aand 192 mg of another compound which was crystallized from pentanegiving 192 mg (33%) of compound 309b.

Preparation of Compound 312, Compound 312a and Compound 312b

To a solution of compound 311 (150 mg; 0.347 mmol),N-diisopropylethylenediamine (52.6 μL; 0.417 mmol) and DIPEA (120 μL;0.695 mmol) in DMF (3 mL) was added COMU (223 mg; 0.521 mmol). Thesolution was stirred at rt for 18 h then combined with another reactionperformed on 50 mg of compound 311. Water and EtOAc were added. Theorganic layer was separated and the aqueous layer was extracted withEtOAc (3×). The combined organic layers were washed with a saturatedaqueous solution of NaCl (3×), dried over MgSO₄, filtered off andevaporated in vacuo.

The crude (438 mg) was purified by silica gel chromatography (Stationaryphase: irregular bare silica 40 g, Mobile phase: 0.5% aq. NEE, 94% DCM,6% MeOH) to give 149 mg of compound 312 as a yellow oil.

Compound 312 was purified by chiral SFC (Stationary phase: CHIRALPAKAD-H 5 μm 250×20 mm, Mobile phase: 65% CO₂, 35% iPOH (0.3% iPrNH₂)) togive 55 mg of impure compound 312a as a yellow oil and 58 mg of impurecompound 312b as a yellow oil. Impure compound 312a was purified bysilica gel chromatography (Irregular SiOH 15-40 μm, 4 g Grace, mobilephase gradient: from DCM 100% to DCM 95%, MeOH/aq NEE (95:5) 5%) to give49 mg of a yellow oil which were solubilized in ACN (1 mL), extendedwith water (9 mL) and freeze-dried to give 46 mg of compound 312a as apale yellow fluffy solid.

Impure compound 312b was purified by silica gel chromatography(Irregular SiOH 15-40 μm, 4 g Grace, mobile phase gradient: from DCM100% to DCM 95%, MeOH/aq NH3 (95:5) 5%) to give 47 mg of a yellow oilwhich were solubilized in ACN (1 mL), extended with water (9 mL) andfreeze-dried to give 45 mg of compound 312b as a pale yellow fluffysolid.

Preparation of Compound 313, Compound 313a and Compound 313b

Compound 313 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312 using compound 311 andN,N,N′-trimethylethylenediamine as starting materials (197 mg). Compound313 was purified by chiral SFC (CHIRALPAK AD-H 5 μm 250×20 mm; mobilephase: 80% CO₂, 20% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and each enantiomer was again purified by silica gelchromatography. The fractions containing the products were mixed and thesolvent was evaporated to give one compound (44 mg) which wasfreeze-dried from pentane and H₂O giving 42 mg (23%) of compound 313aand the other compound (43 mg) which was freeze-dried from pentane andH₂O giving 42 mg (23%) of compound 313b.

Preparation of Compound 314 Compound 314a and Compound 314b

Compound 314 were prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 257a andN-isopropylethylenediamine as starting materials giving 250 mg (57%) ofcompound 314, which was purified by chiral SFC (CHIRALPAK DIACEL AD250×20 mm; mobile phase: CO₂, EtOH-iPrOH 50/50 (0.4% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give 113 mgof one compound which was freeze-dried with pentane and H₂O giving 86 mg(20%) of compound 314a (MP: 80° C., gum, K) and 99 mg of other compoundwhich was freeze-dried with pentane and H₂O giving 79 mg (18%) ofcompound 414b (MP: 80° C., gum, K).

Preparation of Compound 319, Compound 319a and Compound 319b

Compound 319 was prepared and compound 78IPIL were prepared according toan analogous procedure as described for the synthesis of compound 5using compound 291 and (±)-2-(Trifluoromethyl)piperazine as startingmaterials (517 mg; 97%).

Compound 319 was separated by chiral SFC (CHIRALPAK AS-H 5 μm 250×20 mm;mobile phase: 80% CO₂, 20% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and the solvent was evaporated to give one compound (186 mg)which was freeze-dried with pentane and H₂O giving 182 mg (34%) ofcompound 319a and second compound (184 mg) which was freeze-dried withpentane and H₂O giving 166 mg (31%) of compound 319b.

Preparation of Compound 320, Compound 320a and Compound 320b

Compound 320 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 263 and(S)-3-hydroxypiperidine hydrochloride as starting materials (800 mg;94%).

The separation of the enantiomers from 800 mg of compound 320 wasperformed by chiral SFC (CHIRALCEL OJ-H 5 μm 250×20 mm; mobile phase:82% CO₂, 18% EtOH (0.3% iPrNH₂)). The pure fractions were collected andthe solvent was evaporated to give one compound (354 mg) which wascrystallized from DCM and pentane giving 248 mg (29%) of compound 320a(MP: 110° C., K) and a second compound (407 mg) which was crystallizedfrom DCM and pentane giving 300 mg (35%) of compound 320b (MP: 136° C.,K).

Preparation of Compound 321, Compound 321a and Compound 321b:

Compound 321 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 263 and(R)-(+)-3-hydroxypyrrolidine as starting materials (700; 85%).

The separation of the enantiomers from 700 mg of compound 321 was madeby chiral SFC (CHIRALPAK AD-H 5 μm 250×30 mm; mobile phase: 70% CO₂, 30%iPrOH (0.3% iPrNH₂)). The pure fractions were collected and the solventwas evaporated to give one compound (337 mg) which was crystallized fromDCM and pentane giving 262 mg (32%) of compound 321a (MP: 118° C., K)and a second compound (367 mg) which was crystallized from DCM andpentane giving 265 mg (32%) of compound 321b (MP: 128° C., K).

Preparation of Compound 328:

To a solution of compound 327 (200 mg; 0.505 mmol),N,N-dimethylethylenediamine (83 μL; 0.76 mmol) and diisopropylethylamine (174 μL; 1.01 mmol) in DMF (5 mL) was added COMU (324 mg; 0.757mmol). The solution was stirred at room temperature for 1 h. Then, waterand EtOAc were added. The organic layer was separated and the aqueouslayer was extracted with EtOAc (3×). The combined organic layers werewashed with a saturated aqueous solution of NaCl (3×), dried over MgSO,filtered off and evaporated in vacuo. The residue (brown oil) waspurified by silica gel chromatography (Irregular SiOH 15-40 μm, 24 g,mobile phase gradient: from DCM 100% to DCM 90%, MeOH/aq NH₃ (95:5) 10%)to give 252 mg of a yellow oil. This fraction was further purified bysilica gel chromatography (Irregular SiOH 15-40 μm, 10 g, liquid loading(DCM), mobile phase gradient: from heptane 70%, EtOAc/(MeOH/aq. NH₃(95:5)) (80:20) 30%) to heptane 30%, EtOAc/(MeOH/aq. NH₃ (95:5)) (80:20)70%) to give 206 mg of a yellow film which was again further purified bysilica gel chromatography (Irregular SiOH, 15-40 μm, 10 g, dry loading,mobile phase: heptane 80%, EtOAc/(MeOH/aq. NH₃ (95:5)) (80:20) 20%) togive 138 mg of a yellow film. This fraction was triturated in Et₂O. Thesolvent was evaporated in vacuo and the precipitate dried under highvacuum (50° C., 18 h) to give 136 mg (58%) of compound 328 as a yellowsolid (MP: 98° C., DSC).

Preparation of Compound 332

Compound 332 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312 using compound 331 anddimethylamine (solution 2M in THF) as starting materials (96 mg, 50%,MP: 169° C., DSC).

Preparation of Compound 333

Compound 333 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312 using compound 331 andethanolamine as starting materials (80 mg, 68%, MP: 265° C., DSC).

Preparation of Compound 334, Compound 334a and Compound 334b

Compound 334 prepared according to an analogous procedure as describedfor the synthesis of compound 5 using compound 257a and 2-aminoethanolas starting material. The residue (280 mg) was purified bychromatography over silica (irregular SiOH; 15-40 μm; 30 g; gradient:from 95% DCM, 5% MeOH to 93% DCM, 7% MeOH). The pure fractions werecollected and the solvent was evaporated to give 150 mg (54%) ofcompound 334.

The separation of the enantiomers from 150 mg of compound 334 wasperformed by chiral SFC (CHIRALCEL OD-H 5 μm 250×20 mm; mobile phase:70% CO₂, 30% uiPrOH). The pure fractions were collected and the solventwas evaporated to give two fractions which were crystallized from Et₂Oto give respectively 70 mg (16%) of compound 334a (M.P.: 136° C., DSC)and 71 mg (11%) of compound 334b (M.P.: 134° C., DSC).

Preparation of Compound 338, Compound 338a and Compound 338b

Compound 338 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 263 and(2R)-(−)-1-Aminopropan-2-ol as starting material (Crystallization fromDIPE; 360 mg, 72%). The separation of the enantiomers from 309 mg ofcompound 338 was performed by chiral SFC (CHIRALPAK AD-H 5 μm; 250×20mm; mobile phase: 75% CO₂, 25% EtOH). The pure fractions were collectedand the solvent was evaporated, and each fraction was crystallized fromDIPE to afford 112 mg (22%), of compound 338a (M.P.: 90° C. (DSC)) and108 mg (21%) of compound 338b (M.P.: 91° C. (DSC))

Preparation of Compound 342:

A solution of compound 289 (100 mg, 0.25 mmol), HATU (142.45 mg, 0.375mmol) and Et₃N 0.104 mL, 0.749 mmol) in Me-THF (5 mL) was stirred at rtfor 15 min. Then, N-isopropylethylenediamine (47.26 μL, 0.375 mmol) wasadded and the solution was stirred at rt for 5 h. The reaction mixturewas poured in ice water and extracted with EtOAc. The organic layer waswashed with brine (×2), dried over MgSO₄, filtered and evaporated untildryness. The resulting residue was purified via silica gelchromatography (Stationary phase: irregular SiOH 15-40 μm, 40 g, Mobilephase: 95% DCM, 5% MeOH, 0.5% NH4OH) to afford 75 mg (62%) of compound342.

Preparation of Compound 346, Compound 346a, and Compound 346b

Compound 346 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 and(2R)-(−)-1-aminopropan-2-ol as starting material (460 mg; 81%).

The separation of the enantiomers from 460 mg of compound 346 wasperformed via chiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250×20 mm,Mobile phase: 83% CO₂, 17% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and evaporated until dryness and crystallized from pentane togive 115 mg (20%) of compound 346a (M.P.: 107° C. (K)) and 107 mg (19%)of compound 26 (M.P.: 106° C. (K)).

Preparation of Compound 347, Compound 347a and Compound 347b

Compound 347 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 and(R)-1,4-diazabicyclo[4.3.0] nonane as starting material. (1 g; 79%;M.P.: 170° C. (DSC)).

The separation of the enantiomers from 950 mg of compound 347 wasperformed via chiral SFC (Stationary phase: Chiralpak AS-H 5 μm 250*20mm, Mobile phase: 50% CO₂, 50% MeOH (0.3% iPrNH₂)). The pure fractionswere collected and evaporated until dryness and crystallized from amixture of pentane/DCM (19/1) to give 400 mg (32%) of compound 347a(M.P.: 125° C. (K)) and 317 mg (30%) of compound 347b (M.P.: 125° C.(K)).

Preparation of Compound 348, Compound 348a and Compound 348b

Compound 348 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 and1-amino-2-methyl-2-propanol as starting materials (540 mg; 92%).

The separation of the enantiomers from 540 mg of compound 348 wasperformed via SFC (Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm,Mobile phase: 86% CO₂, 14% EtOH (0.3% iPrNH₂)). The pure fractions werecollected and evaporated until dryness and crystallized from pentane togive 157 mg (27) of compound 348a (M.P.: 102° C. (K)) and 173 mg (30%)of compound 348b (M.P.: 102° C. (K)).

Preparation of Compound 349, Compound 349a and Compound 349b

Compound 349 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 andN,N,N′-Trimethylenediamine as starting materials (480 mg; 80%).

The separation of the enantiomers from 480 mg of compound 349 wasperformed via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20mm, Mobile phase: 83% CO₂, 17% EtOH (0.3% iPrNH2)). The pure fractionswere collected and evaporated until dryness and crystallized frompentane to give 131 mg (22%) of compound 349a (M.P.: 82° C. (K)) and 131mg (22%) of compound 349b (M.P.: 82° C. (K)).

Preparation of Compound 353:

Compound 353 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 285 andN,N,N′-tri methyl ethylene diamine as starting material (350 mg, 58%,80° C., (K)).

Preparation of Compound 354:

Compound 354 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 307 as startingmaterial (72 mg, 41%),

Preparation of Compound 357, Compound 357a and Compound 357b

Compound 357 prepared according to an analogous procedure as describedfor the synthesis of compound 5, using compound 234 and cis2,6-dimethylpiperazine as starting materials (570 mg; 92%).

The separation of the enantiomers from 570 mg of compound 357 wasperformed via SFC (Chiralpak AS-H 5 μm 250*20 mm, Mobile phase: 45% CO₂,55% EtOH (0.3% iPrNH₂)) The pure fractions were collected and thesolvent was evaporated. Each fraction was crystallized from pentane togive, after filtration, 191 mg (31%) of compound 43 (M.P.: 116° C. (K))and 170 mg (38%) of compound 44 b (M.P.: 120° C. (K))

Preparation of Compound 358:

Compound 358 was prepared according to an analogous procedure asdescribed for the preparation of compound 5, using compound 291 anddimethylamine as starting materials (126 mg of 60%).

Preparation of Compound 363 Compound 363a and Compound 363b

Compound 363 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 starting from compound 285 and(S)-(+)-3-(dimethylamino)pyrolidine

The separation of the enantiomers was performed by SFC (Stationaryphase: Chiralpak Diacel AD 20×250 mm, Mobile phase: CO₂, iPrOH+0.4iPrNH₂). The pure fractions were mixed and concentrated to afford 20 mg(5%) of compound 363a (M.P.: 80° C., gum K) and 70 mg (19%) of compound363b (M.P.: 80° C., gum K)

Preparation of Compound 364, Compound 364a and Compound 364b

Compound 364 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 234 andN-isopropylehtylenediamine as starting materials (280 mg, 58%, M.P.: 80°C. gum (K)).

The separation of the enantiomers was performed by chiral SFC (CHIRALPAKAD-H 5 μm; 250×20 mm; mobile phase: 60% CO₂, 40% EtOH (0.3% iPrNH2)).The pure fractions were collected and the solvent was evaporated. Eachfraction was crystallized from a mixture of DCM/Et20 and gave, afterfiltration, 90 mg (18%) of compound 364a (M.P.: 80° C., gum (K)) and 89mg (18%) of compound 364b (M.P.: 80° C., gum (K)).

Preparation of Compound 366:

Compound 366 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 307 as startingmaterial (154 mg, 66%).

Preparation of Compound 367, Compound 367a and Compound 367b

Compound 367 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5 using compound 307 and(+/−)-2-(Trifluoromethyl)piperazine as starting material (453 mg, 85%).

The separation of the enantiomers from 453 mg of compound 367 wasperformed chiral SFC (CHIRALPAK AD-H 5 μm; 250×30 mm; mobile phase: 70%CO₂, 30% EtOH (0.3% iPrNH₂)). The pure fractions were collected and eachfraction was crystallized from a mixture of Pentane/Et2O to give, afterfiltration, 119 mg (22%) of compound 367a and 127 mg (24%) of compound367b.

Preparation of Compound 369, Compound 369a and Compound 369b

Compound 369 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 285 and(6S)-1,4-diazabicyclo[4.3.0]nonane as starting materials (800 mg; 96%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: Chiralpak Diacel AD 20×250 mm, Mobile phase: CO₂,EtOH+0.4 iPrNH₂). The pure fractions were mixed and concentrated toafford fraction A (470 mg) and fraction B (450 mg). Fraction A was takenup with a mixture of Et₂O/pentane. The precipitate was filtered toafford 180 mg (22%) of compound 369a (22%). Fraction B was taken up witha mixture of DCM/pentane. The precipitate was filtered to afford 140 mg(17%) of compound 369b (M.P.: 147° C., (DSC K)).

Preparation of Compound 375:

Compound 375 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 285 and(R)-1,4-Diazabicyclo[4.3.0]nonane as starting materials (250 mg, 20%,M.P: 80° Gum (K)).

Preparation of Compound 381:

Compound 381 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312 using compound 327 and2-aminoethanol as starting materials. (162 mg, 73%).

Preparation of Compound 382:

Compound 382 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312 broux using compound 327 anddimethyl amine (2M solution in THF) as starting materials (136 mg, 64%,M.P: 150° C. (DSC)).

Preparation of Compound 384:

Compound 384 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 289 andN,N-dimethylethylenediamine as starting materials (66 mg, 19%).

Preparation of Compound 392, Compound 392a and Compound 392b

Compound 392 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 263 andglycine ethyl ester hydrochloride as starting materials (727 mg, 66%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂,40% EtOH (0.3% iPrNH₂)). The fractions containing the products wereconcentrated to afford, after freeze-drying in a mixture of ACN/water(20/80), 220 mg (20%) of compound 392a (MP: 80° C., gum, Kofler) and 215mg (20%) of compound 392b.

Preparation of Compound 394:

Compound 394 was prepared according to an analogous procedure asdescribed for the synthesis of compound 312, using compound 331 andN,N-dimethylethylenediamine as starting materials (86 mg, MP: 161° C.(DSC)).

Preparation of Compound 407, Compound 407a, Compound 407b

Compound 407 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 294 andN,N-dimethylethylenediamine as starting materials (588 mg, 85%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 60% CO₂,40% EtOH (0.3% iPrNH₂)). The fractions containing the products wereconcentrated to afford, after freeze-drying in a mixture of ACN/water(20/80), 232 mg (34%) of compound 407a (MP: 115° C., Kofler) and 170 mg(25%) of compound 407b (MP: 105° C., Kofler).

Preparation of Compound 408, Compound 408a and Compound 408b

Compound 408 was prepared according to an analogous procedure asdescribed for the synthesis of compound 5, using compound 263 andethanol-1,1,2,2-d4-amine as starting materials (400 mg, 71%).

The separation of the enantiomers was performed by chiral SFC(Stationary phase: CHIRALPAK IC 5 μm 250×30 mm, Mobile phase: 55% CO₂,45% iPOH (0.3% iPrNH₂)). The fractions containing the products wereconcentrated to afford, after crystallization from EtOH, 161 mg (28%) ofcompound 408a (MP: 127° C., DSC) and 131 mg (22%) of compound 408b (MP:123° C., DSC).

Coversion C2

Preparation Compound 10:

Diisobutylaluminium hydride (solution 20% in toluene) (15.8 mL; 3.79mmol) was added dropwise to a solution of compound 249 (860 mg; 1.89mmol) in THF (50 mL) at −70° C. under N₂. The mixture was stirred at−70° C. for 1 h30. The solution was poured into ice-water. EtOAc wasadded and the mixture was filtered through a pad of Celite®. The productwas extracted with EtOAc. Then, the organic layer was dried over MgSO₄,filtered and evaporated to dryness. The residue (820 mg) was purified bychromatography over silica gel (irregular bare silica 40 g; mobilephase: 97% DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions were collectedand the solvent was evaporated to give 594 mg which was recrystallizedwith diethylether. The precipitate was filtered and dried to give 425 mg(52%) of compound 10. M.P.: 189° C. (DSC).

Preparation Compound 88 and Compound 89

Compound 88 and compound 89 were prepared according to an analogousprocedure as described for the synthesis of compound 10, using compound257a as starting materials. After purification by chromatography oversilica gel (irregular SiOH; 15-40 μm; 30 g; gradient: from 65% heptane,31.5% EtOAc, 3.5% MeOH to 30% heptane, 63% EtOAc, 7% MeOH), theresulting residue (409 mg, pale yellow foam) was purified by chiral SFC(CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 75% CO₂, 25% MeOH). Thepure fractions were collected and the solvent was evaporated to give twofractions which were separately co-evaporated in DCM (×2) and driedunder reduced pressure (16 h, 50° C.) to give respectively 144 mg (28%,pale yellow foam) of compound 88 and 160 mg (30%, pale yellow foam) ofcompound 89.

Preparation Compound 111

Diisobutylaluminium hydride (solution 20% in toluene) (1.96 mL; 0.47mmol) was added dropwise to a solution of compound 97 (100 mg; 0.24mmol) in THF (7 mL) at −70° C. under N₂. The mixture was stirred at −70°C. for 2 h. The solution was poured into ice-water. EtOAc was added andthe mixture was filtered through a pad of Celite®. The product wasextracted with EtOAc. Then the organic layer was dried over MgSO₄,filtered and evaporated to dryness. The residue (100 mg) was purified bychromatography over silica gel (irregular bare silica 10 g; mobilephase: 97% DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions were collectedand the solvent was evaporated. The residue (59 mg; impure compound 111)was taken-up with DCM. Oxygen was bubbled in the solution for 30 min andthe solution was stirred at rt overnight. Then, the solution wasevaporated to dryness. The residue (54 mg) was purified by reverse phase(X-Bridge-C18 5 μm; 30*150 mm; gradient: from 65% NH₄HCO₃ 0.5%, 35% ACNto 25% NH₄HCO₃ 0.5%, 75% ACN). The pure fractions were collected and thesolvent was evaporated to give 30 mg (32%) of compound 111. M.P.: 80° C.(K).

Preparation Compound 84, Compound 154a and Compound 154b

Compound 84, compound 154a and compound 154b were prepared according toan analogous procedure as described for the synthesis of compound 111,using compound 80 as starting material. Compound 84 (2.6 g) was purifiedby chiral SFC (CHIRALCEL OJ-H; 5 μm 250×20 mm; mobile phase: 65% CO₂,35% EtOH (0.3% iPrNH₂)). The pure fractions were collected and thesolvent was evaporated to give two fractions, which were separatelytaken-up in diethylether and heptane, filtered and dry under vacuum togive respectively 220 mg (5%) of compound 154a and 210 mg (5%) ofcompound 154b. M.P.: 90° C. (K).

Preparation of Compound 303:

Compound 303 was prepared according to an analogous procedure asdescribed for the synthesis of compound 10 using compound 233 (asstarting material. (100 mg, 33%, MP:138° C., DSC).

Conversion C3

Preparation of Compound 45:

NaBH₄ (7 mg; 0.19 mmol) was added to a solution of compound 44 (90 mg;0.19 mmol) in MeOH (2 mL) at 5° C. The reaction mixture was stirred at5° C. for 4 h. The mixture was poured into H₂O, filtered through a padof Celite® and extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and evaporated until dryness. The residue (110 mg) waspurified by chromatography over silica gel (irregular 15-40 μm; 30 g;mobile phase: 97% DCM, 3% MeOH, 0.1% NH₄OH). The pure fractions werecollected and evaporated until dryness. The residue (65 mg) wasfreeze-dried with water/ACN 80/20 to give 62 mg (69%, yellow solid) ofcompound 45. M.P.: 80° C. (gum, K).

Conversion C4

Preparation compound 14:

2-aminoethanol (0.21 mL; 3.53 mmol) was added to a solution of compound250 (150 mg; 0.35 mmol) in MeOH (7 mL) and the reaction mixture wasstirred at rt for 4 h. Then sodium borohydride (20 mg; 0.53 mmol) wasadded portionwise at 0° C. and the reaction mixture was stirred at rtfor 1 h30. Water was added and the product extracted with EtOAc. Theorganic layer was washed with brine (2×), dried over MgSO₄, filtered andevaporated to dryness. The residue (200 mg) was purified bychromatography over silica gel (irregular 15-40 μm; mobile phase: 90%DCM, 10% MeOH, 0.1% NH₄OH). The pure fractions were collected and thesolvent was evaporated to give 145 mg (88%) of compound 14. M.P.: 140°C. (K).

Preparation Compound 76:

Compound 250 (100 mg; 0.24 mmol) was added to a solution of3-hydroxyazetidine hydrochloride (258 mg; 2.36 mmol) and sodium acetate(193 mg; 2.36 mmol) in MeOH (3 mL). The reaction mixture was stirred atrt for 4 h. Then, sodium borohydride (18 mg; 0.47 mmol) was addedportionwise at 0° C. and the reaction mixture was stirred at rt for 1h30. Water was added and the product extracted with EtOAc. The organiclayer was washed with brine (2×), dried over MgSO₄, filtered andevaporated to dryness. The residue (210 mg) was purified bychromatography over silica gel (irregular 15-40 μm; 24 g; mobile phase:90% DCM, 10% MeOH, 0.1% NH₄OH). The pure fractions were collected andthe solvent was evaporated to give 115 mg (100%) of compound 76. M.P.:90° C. (DSC).

Preparation Compound 77:

Compound 77 was prepared according to an analogous procedure asdescribed for the synthesis of compound 76, using compound 250 andL-prolinol as starting materials (freeze-dried: 48 mg, 80%). M.P.: 80°C. (gum, K).

Preparation Compound 101:

Compound 101 was prepared according to an analogous procedure asdescribed for the synthesis of compound 76, using compound 250 and2-(methylamino)ethanol as starting materials (72 mg, 63%). M.P.: 80° C.(gum, K).

Preparation Compound 102:

Compound 102 was prepared according to an analogous procedure asdescribed for the synthesis of compound 14, using compound 250 and3-amino-1-propanol as starting materials (55 mg, 48%). M.P.: 80° C.(gum, K).

Preparation Compound 103:

Compound 103 was prepared according to an analogous procedure asdescribed for the synthesis of compound 14, using compound 250 and2-methoxyethylamine as starting materials (83 mg, 73%). M.P.: 80° C.(gum, K).

Preparation Compound 112:

Compound 112 was prepared according to an analogous procedure asdescribed for the synthesis of compound 76, using compound 250 andN-(2-(methoxyethyl)methylamine as starting materials (76 mg, 22%). M.P.:80° C. (gum, K).

Coversion C5

Preparation Compound 48:

Compound 48 was prepared according to an analogous procedure asdescribed for the synthesis of compound 14, using compound 44 andD-alaninol as starting materials (freeze-dried: 27 mg, 48%). M.P.: 80°C. (gum, K).

Preparation Compound 49:

Compound 49 was prepared according to an analogous procedure asdescribed for the synthesis of compound 14, using compound 44 andisopropylamine as starting materials (freeze-dried: 14 mg, 21%). M.P.:80° C. (gum, K).

Preparation Compound 67:

Compound 67 was prepared according to an analogous procedure asdescribed for the synthesis of compound 14, using compound 44 andD-alaninol as starting material (freeze-dried: 25 mg, 20%). M.P.: 80° C.(gum, K).

Coversion C6

Preparation of Compound 251:

A solution of lithium hydroxide monohydrate (370 mg; 8.8 mmol) in water(3 mL) was added to a mixture of compound 249 (400 mg; 0.88 mmol) in THF(12 mL) at rt. The reaction mixture was heated at 50° C. for 15 h. Themixture was cooled down to rt. Ice-water was added and the solution wasslowly acidified with a 3N aqueous solution of HCl. A precipitate wasfiltered, washed with Et₂O and dried to give 226 mg of fraction 1. Thefiltrate was extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and evaporated. The residue (88 mg) was combined withfraction 1 (226 mg) and the resulting residue (314 mg) was purified byreverse phase (X-Bridge-C18 5 μm; 30*150 mm; gradient: from 75% NH₄HCO₃0.5%, 25% ACN to 35% NH₄HCO₃ 0.5%, 65% ACN). The pure fractions werecollected and the solvent was evaporated to give 196 mg (51%) ofcompound 251. M.P.: 299° C. (DSC).

Preparation of Compound 62:

Compound 62 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 254 asstarting material (1.05 g, 86%; after recrystallization from 150 mg: 58mg, 5% of compound 62. M.P.: >260° C. (K).

Preparation of Compound 83a, Compound 83b and Compound 83c

Compound 83a, compound 83b and compound 83c were prepared according toan analogous procedure as described for the synthesis of compound 251,using compound 80 as starting material. A first reaction gave 56 mg(41%) of compound 83a. M.P.: 240° C. (DSC). A second reaction gave 1.3 gof compound 83a was further purified by chiral SFC (Chiralpak IA 5 μm;250*20 mm; mobile phase: 60% CO₂, 40% iPrOH (0.3% iPrNH₂)). The purefractions were collected and the solvent was evaporated to give twofractions which were separately taken-up with H₂O, acidified with 3Naqueous solution of HCl. The precipitate were filtered, washed with H₂Oand diethylether and dried to give respectively 287 mg (26%) of compound83b (M.P.: 180° C., DSC) and 278 mg (25%) of compound 83c (M.P.: 157°C., DSC).

Preparation of Compound 98:

Compound 98 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 97 asstarting material (after recrystallization: 177 mg, 77%. M.P.: 240° C.(DSC).

Preparation of Compound 170:

Compound 170 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 266 asstarting material (1.15 g, 88%. M.P.: 285° C. (DSC).

Preparation of Compound 234:

Compound 234 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 233 asstarting material (8.57 g, 95%).

Preparation of Compound 236:

Compound 236 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 235 asstarting material. (11 g; 96%) of compound 236. M.P: 240° C. (DSC)

Preparation of compound 239:

Compound 239 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 272a asstarting material. The reaction was stirred at rt overnight. (44 mg;52%) of compound 239.

Preparation of Compound 240:

1.73 H₂O 0.68 HCl Compound 240 was prepared according to an analogousprocedure as described for the synthesis of compound 251, using compound272b as starting material. The reaction was stirred at rt overnight. (42mg; 50%) of compound 240 (1.73 H₂O 0.68 HCl).

Preparation of Compound 241:

Compound 241 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 273a asstarting material. The reaction was stirred at rt overnight. (76 mg;73%) of compound 241.

Preparation of Compound 242:

Compound 242 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 273b asstarting material. The reaction was stirred at rt overnight. (76 mg;73%) of compound 242.

Preparation compound 248:

To a solution of compound 248 (1.36 g, 2.05 mmol) in THF (10 mL) andMeOH (10 mL) was added an aqueous solution of NaOH (6.16 mL, 1 M, 6.16mmol). The mixture was stirred at rt over the weekend. The mixture wasevaporated and the resulting residue was slowly acidified with anaqueous solution of HCl (1N). The precipitate was filtered to give 797mg (93%; yellow oil) of compound 248.

Preparation of Compound 253:

Compound 253 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 252 asstarting material (200 mg, 88%). The product was used withoutpurification in the next step.

Preparation of Compound 257a, Compound 257b and Compound 257c

Compound 257a was prepared according to an analogous procedure asdescribed for the synthesis of compound 248, using compound 256 asstarting material. The reaction mixture was heated at 50° C. for 1 h.The mixture was cooled down to rt and evaporated in vacuum. The residuewas slowly acidified with 1N aqueous solution of HCl, filtered and driedunder vacuum. Compound 257a (994 mg, 98%, yellow solid) was purified bychiral SFC (Chiralpak AD-H 5 μm 250*30 mm; mobile phase: 80% CO₂, 20%iPrOH (0.3% iPrNH₂)). The pure fractions were collected and the solventwas evaporated to give 196 mg (yellow oil) of fraction 1 and 145 mg(yellow oil) of fraction 2. Fraction 1 was purified by chromatographyover silica gel (irregular SiOH; 15-40 μm; 10 g; gradient: from 96% DCM,4% MeOH/NH₄OH (95/5) to 82% DCM, 18% MeOH/NH₄OH (95/5)). The purefractions were collected and the solvent was evaporated. The residue(109 mg, pale yellow oil) was purified by reverse phase (X-Bridge-C18 5μm 30*150 mm; gradient: from 85% (aq. NH₄HCO₃ 0.5%), 15% ACN to 45% (aq.NH₄HCO₃ 0.5%), 55% ACN). The pure fractions were collected and thesolvent was evaporated. The residue was co-evaporated in DCM/pentane(1/4) and dried under vacuum (50° C., 16 h) to give 66 mg (7%, paleyellow solid) of compound 257b. Fraction 2 was purified bychromatography over silica gel (irregular SiOH; 15-40 μm; 10 g;gradient: from 96% DCM, 4% MeOH/NH₄OH (95/5) to 80% DCM, 20% MeOH/NH₄OH(95/5)). The pure fractions were collected and the solvent wasevaporated. The residue was triturated in DCM/pentane (1/4), filteredand dried under vacuum (50° C., 16 h) to give 119 mg (12%, pale yellowsolid) of compound 257c.

Preparation of Compound 261:

Compound 261 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 260 asstarting material (280 mg, 90%, yellow solid).

Preparation of Compound 263:

Compound 263 was prepared according to an analogous procedure asdescribed for the synthesis of compound 248, using compound 262 asstarting material (577 mg, 96%, yellow solid).

Alternative Pathway:

Compound 263 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 262 asstarting material (217 mg, quant.). The reaction mixture was stirred at50° C. for 15 h. The product was used without purification for the nextstep.

Preparation of Compound 265:

Compound 265 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 264 asstarting material (170 mg, 47%, yellow solid). The product was usedwithout purification in the next step.

Preparation of Compound 270:

Compound 270 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251 using compound 269 asstarting material (890 mg; 100%). The product was used withoutpurification for the next step.

Preparation of Compound 285:

Compound 285 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251 using compound 209 asstarting material (3.5 g, 90%).

Preparation of Compound 289:

Compound 289 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 288 asstarting material (3.98 g, 84%).

Preparation of Compound 291:

compound 291 was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 290 asstarting material (300 mg, 48%).

Preparation of Compound 294:

Compound 294 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25 Fusing compound 293 asstarting material (3.8 g, 95%).

Preparation of Compound 307:

Compound 307 was prepared according to an analogous procedure asdescribed for the synthesis of compound 83a using compound 306 asstarting material (2.8 g; 113%).

Preparation of Compound 311:

Compound 311 was prepared according to an analogous procedure asdescribed for the synthesis of compound 248 using compound 310 asstarting material (1 g, 59%).

Preparation of Compound 327:

To a suspension of compound 326 (1.52 g; 3.70 mmol) in MeTHF (15 mL) andMeOH (15 mL) was added a 1M aqueous solution of sodium hydroxide (22.2mL; 22.2 mmol). The mixture was heated at 40° C. for 1 h then at 50° C.for 1 h. After cooling down to rt, the crude was concentrated in vacuo.The residue was slowly acidified with a 1N aqueous solution of HCl(until pH #4) and the precipitate formed was filtered on a glass frit.The solid was taken up in EtOH and evaporated in vacuo to give 900 mg(61%) of compound 327 as a yellow solid.

Preparation of Compound 331:

Compound 331 was prepared according to an analogous procedure asdescribed for the synthesis of compound 327 using compound 330 asstarting material (298 mg, 61%).

Preparation of Compound 378:

Compound 378 (was prepared according to an analogous procedure asdescribed for the synthesis of compound 248, using compound 377 asstarting material (1.67 g, 99%).

Preparation of Compound 393 a:

Compound 393a was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 393a asstarting material (108 mg, 57%, MP: 115° C., gum, Kofler).

Preparation of Compound 393b:

Compound 393b was prepared according to an analogous procedure asdescribed for the synthesis of compound 251, using compound 393b asstarting material (110 mg, 51%, MP: 196° C., DSC).

Conversion C7

Preparation of Compound 186 and Compound 187

At 0° C., thionyl chloride (0.5 mL; 7.21 mmol) was added to a solutionof compound 169 (350 mg; 0.72 mmol) in DCM (7 mL). The reaction mixturewas stirred at rt overnight. The mixture was poured into ice and 10%aqueous solution of K₂CO₃, then extracted with EtOAc. The organic layerwas washed with brine, dried over MgSO₄, filtered and evaporated untildryness. The residue (320 mg) was combined with another batch comingfrom a reaction performed on 206 mg of compound 169. The two residueswere purified together by column chromatography over silica gel (40 g,mobile phase; from 100% DCM to 97% DCM, 3% MeOH, 0.3% NH₄OH). The purefractions were collected and evaporated. The residue (333 mg) waspurified by chiral SFC (CHIRALCEL OJ-H 5 μm 250×20 mm; mobile phase: 80%CO₂, 20% EtOH (0.3% iPrNH₂)). The pure fractions were collected andevaporated to give 136 mg (25%) of compound 186 (M.P.: 80° C. (gum, K))and 139 mg (26%) of compound 187 (M.P.: 80° C. (gum, K)).

Conversion C8

Preparation of Compound 225:

A mixture of compound 271 (200 mg; 0.50 mmol), hydroxylaminehydrochloride (105 mg; 1.51 mmol) in EtOH (10 mL) and water (3 mL) washeated at 100° C. for 5 h. The mixture was poured into water andextracted with DCM. The organic layer was dried over MgSO₄, filtered andevaporated to dryness. The residue (200 mg) was purified bychromatography over silica gel (irregular SiOH 15-40 μm; 300 g; mobilephase: 96% DCM, 4% MeOH, 0.1% NH₄OH). The pure fractions were collectedand the solvent was evaporated. The residue (110 mg) was crystallizedfrom diethylether. The yellow precipitate was filtered off and dried togive 75 mg (36%) of compound 225. M.P.: 80° C. (gum, K).

Conversion C9

Preparation of Compound 290:

NaH (60% dispersion in mineral oil) (202.7 mg, 5.07 mmol) was addedportion wise to a solution of compound 289 (1 g, 2.41 mmol) in DMF (10mL) under nitrogen at 0-5° C. (ice bath cooling). The mixture wasstirred at 0-5° C. for 15 mn then, iodomethane (300 μL, 4.83 mmol) wasadded. The reaction mixture was stirred at room temperature for 16 h,poured onto iced water and extracted with EtOAc, the organic layer waswashed with water, dried over MgSO₄ and evaporated to dryness, Theresidue was purified by silica gel chromatography to give 650 mg (63%)of compound 290.

Preparation of Compound 306:

NaH (60% dispersion in miral oil; 1.023 g, 25.582 mmol) was addedportionwise to a solution of compound 305 (5 g, 12.18 mmol) in DMF (50mL) under nitrogen at 0-5° C. (ice bath cooling). The mixture wasstirred at 0-5° C. for 15 mn then, iodomethane (1.52 mL, 24.36 mmol) wasadded. The reaction mixture was stirred at room temperature for 16 h.The reaction mixture was poured into cooled water. The product wasextracted with AcOEt and the organic layer was evaporated to dryness.The residue (6.6 g) was purified by silica gel chromatography (120 g ofSiOH 20-45 μm, gradient from 40/60 to 10/90 Heptane/EtOAc). Thefractions were collected and evaporated until dryness to afford 1.9 g(37%) of compound 306.

Conversion C10

Preparation of Compound 341:

Under N₂ at 10° C., methylmagnesium bromide 3M in Et₂O (467 μL; 1.4mmol) was added to a solution of compound 80 (300 mg, 0.7 mmol) in THF(12 mL). The solution was stirred at 10° C. for 2 hours. The solutionwas cooled and the mixture was poured into cooled water and a 10% NH₄Clsolution. The product was extracted with EtOAc. The organic layer wasseparated, dried over MgSO₄, filtered and evaporated to dryness. Theresidue (300 mg) was purified via silica gel chromatography (Stationaryphase: irregular bare silica 40 g, Mobile phase: 98% DCM, 2% MeOH, 0.1%NH₄OH). The pure fractions were collected and the solvent wasevaporated. The residue was freeze-dried with acetonitrile/water (20/80)to give 40 mg (13%) of compound 341 as yellow powder. M.P.: 80° C., gum,K.

Conversion C11

Preparation of Compound 360 and Compound 361

Compound 351 (210 mg, 0.435 mmol), 2-iodopropane (47.87 μL, 1.7 g/mL,0.479 mmol) and Cs₂CO₃ (425.393 mg, 1.306 mmol) in ACN (10 mL) werestirred at 80° C. for 18 h. Then, the mixture was poured into water andextracted with EtOAc. The organic layer was dried over MgSO₄, filteredoff and evaporated in vacuo. The residue (325 mg) was purified by silicagel chromatography (12 g of SiOH 15 μm, gradient from 98/2/0.2 to90/10/1). The fractions were collected and evaporated until dryness togive 90 mg (39%) of compound 360 and 30 mg (12%) of compound 361.

Preparation of Compound 373:

Compound 373 was prepared according to an analogous procedure asdescribed for the synthesis of compound 360 using compound 372 asstarting material (105 mg; 92%). Preparation of compound 388, compound388a and 388b

Compound 388 was prepared according to an analogous procedure asdescribed for the synthesis of compound 360 using compound 387 asstarting material (90 mg; 28%). The separation of the enantiomers from90 mg of compound 388 was performed by chiral SFC (CHIRALPAK AD-H 5 μm250×20 mm; mobile phase: 70% CO₂, 30% iPrOH (0.3% iPrNH₂). The purefractions were collected and the solvent was evaporated to give, afterfreeze-drying, 46 mg (14%) of compound 388a and 47 mg (14%) of compound388b.

Coversion C12

Preparation of Compound 117a

Compound 117 (1 g; 2.17 mmol) was dissolved in isopropanol (32 mL) atroom temperature. Then, a solution of sulfuric acid (58 μL; 1.082 mmol)was added dropwise. A precipitate appeared slowly and the mixture wasstirred for 2 hours at room temperature. The precipitate was filteredand dried at 60° C. under vacuum to give 693 mg (58%) of compound 117a(MP: 179° C., DSC).

Preparation of Compound 118a

Compound 118 (0.5 g; 1.14 mmol) was dissolved in MeTHF (20 mL) at roomtemperature. Then, a solution of HCl, 4M in dioxane (284 μL; 1.14 mmol)was added dropwise. A precipitate appeared slowly and the mixture wasstirred for overnight at room temperature. The precipitate was filteredand dried at 60° C. under vacuum to give 411 mg (75%) of compound 118a.

Preparation of Compound 184a

At 0° C., a solution of HCl, 4M in dioxane (516 μL; 2.06 mmol) was addedto a solution of compound 184 (0.5 g; 1.03 mmol) dissolved in MeOH (10mL). The solution was allowed to reach slowly room temperature andstirred for several days. Et₂O was added; the red precipitate wasfiltered and dried to give 554 mg (87%) of compound 184a (gum at 80° C.,K).

Preparation of Compound 184b

At 0° C., sulfuric acid (33 μL; 0.619 mmol) was added to a solution ofcompound 184 (0.3 g; 0.619 mmol) dissolved in EtOH (3 mL). The solutionwas allowed to reach slowly room temperature and stirred overnight. Et₂Owas added; the precipitate was filtered and dried to give 360 mg (97%)of compound 184b (MP: 270° C.; DSC).

Preparation of Compound 184c

At 0° C., methane sulfonic acid (40 μL; 0.619 mmol) was added to asolution of compound 184 (0.3 g; 0.619 mmol) dissolved in EtOH (3 mL).The solution was allowed to reach slowly room temperature and stirredovernight. Et₂O was added; the yellow precipitate was filtered and driedto give 320 mg (89%) of compound 184c (MP: 74° C., DSC).

Analytical Part

LCMS (Liquid Chromatography/Mass Spectrometry)

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.Compounds are described by their experimental retention times (Rt) andions. If not specified differently in the table of data, the reportedmolecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or[M−H]⁻ (deprotonated molecule). In case the compound was not directlyionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]⁻,etc. . . . ). For molecules with multiple isotopic patterns (e.g. Br,Cl), the reported value is the one obtained for the lowest isotope mass.All results were obtained with experimental uncertainties that arecommonly associated with the method used. Hereinafter, “SQD” meansSingle Quadrupole Detector, “RT” room temperature, “BEH” bridgedethylsiloxane/silica hybrid, “DAD” Diode Array Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Flow Run Method code InstrumentColumn Mobile phase gradient Column T time Method 1 Waters: AcquityWaters: BEH A: 95% 84.2% A for 0.49 min, 0.343 6.2 UPLC ® - DAD and C18(1.7 μm, CH₃COONH₄ to 10.5% A in 40 Quattro Micro ™ 2.1 × 100 mm) 7mM/5% 2.18 min, held for CH₃CN, 1.94 min, back to B: CH₃CN 84.2% A in0.73 min, held for 0.73 min. Method 2 Waters: Acquity Waters: BEH A: 95%From 84.2% A to 0.343 6.1 UPLC ® H-Class - C18 (1.7 μm, CH₃COONH₄ 10.5%A in 2.18 40 DAD and SQD 2 2.1 × 100 mm) 7 mM/5% min, held for CH₃CN,1.94 min, back to B: CH₃CN 84.2% A in 0.73 min, held for 0.73 min.Method 3 Waters: Alliance ® - Waters Atlantis ® A: 50% A/0% B for 0.8 12DAD and ZQ ™ C18 (5 μm, CH₃COONH₄ 1.5 min, to 10% A/80% 30 3.9 × 100 mm)7 mM, B in 3.5 min, held for B: CH₃CN, 4 min, back to C: 0.2% HCOOH 50%A/0% B in 1.5 min, held for 1.5 min.

DSC

For a number of compounds, melting points (MP) were determined with aDSC1 (Mettler-Toledo). Melting points were measured with a temperaturegradient of 10° C./minute. Maximum temperature was 350° C. Values arepeak values.”

For a number of compounds, melting points were obtained with a Koflerhot bench, consisting of a heated plate with linear temperaturegradient, a sliding pointer and a temperature scale in degrees Celsius.

NMR The NMR experiments were carried out using a Bruker Avance 500 IIIusing internal deuterium lock and equipped with reverse triple-resonance(¹H, ¹³C, ¹⁵N TXI) probe head or using a Bruker Avance DRX 400spectrometer at ambient temperature, using internal deuterium lock andequipped with reverse double-resonance (¹H, ¹³C, SEI) probe head with zgradients and operating at 400 MHz for the proton and 100 MHz forcarbon. Chemical shifts (5) are reported in parts per million (ppm).

OR

Optical Rotation (OR) is measured with a polarimeter 341 Perkin Elmer.The polarized light is passed through a sample with a path length of 1decimeter and a sample concentration of 0.2 to 0.4 gram per 100milliliters. 2 to 4 mg of the product in vial are weight, then dissolvedwith 1 to 1.2 ml of spectroscopy solvent (e.g. Dimethylformamide). Thecell is filled with the solution and put into the polarimeter at atemperature of 20° C. The OR is read with 0.004° precision.

Calculation of the concentration: weight in gram×100/volume in ml

[α]_(d) ²⁰: (read rotation×100)/(1.000 dm×concentration).

^(d) is sodium D line (589 nanometer).

TABLE Co. No. means compound number; Retention time (R_(t)) in min; MPmeans melting point (° C.); dec means decomposition; n.d. means notdetermined. Kofler [M + H]⁺ or MP (K) or [M + Na]⁺ or Method Co. No. (°C.) DSC Rt fragments HPLC  1 100 K 3.10 468 1  2 80 (gum) K 3.11 468 1 3 n.d. — 3.27 482 1  4 n.d. — 3.26 482 1  5 n.d. — 2.98 443 1  6 n.d. —2.98 443 1  7 206 DSC 2.80 484 1  8 100 (gum)  K 2.80 484 1  9 n.d. —2.80 484 1  10 189 DSC 3.06 427 1  11 228 DSC 2.82 442 1  12 218 DSC2.82 442 1  13 217 DSC 2.82 442 1  14 140 K 2.69 470 1  15 80 (gum) K3.18 441 1  16 80 (gum) K 3.18 441 1  17 170 K 2.64 497 1  18 80 (gum) K2.69 511 1  19 80 (gum) K 2.64 470 1  20 80 (gum) K 3.04 494 1  21 184DSC 2.78 438 1  22 183 DSC 2.78 438 1  23 n.d. — 3.05 398 1  24 100(gum)  K 3.05 398 1  25 98 (gum) K 3.05 398 1  26 80 (gum) K 3.10 468 1 27 80 (gum) K 3.06 432 1  28 80 (gum) K 3.06 450 1  29 n.d. — 3.22 4641  30 n.d. — 3.23 464 1  31 213 DSC 3.49 455 1  32 80 (gum) K 3.03 480 1 33 280 DSC 3.12 480 1  34 160 K 2.92 570 1  35 80 (gum) K 3.23 464 1 36 n.d. — 3.28 482 1  37 276 DSC 3.12 480 1  38 146 K 2.95 558 1  39 80(gum) K 2.84 537 1  40 80 (gum) K 2.96 454 1  41 80 (gum) K 2.98 462 1 42 80 (gum) K 3.07 450 1  43 80 (gum) K 2.93 558 1  44 80 (gum) K 2.85478 1  45 80 (gum) K 2.57 480 1  46 80 (gum) K 2.83 537 1  47 80 (gum) K2.92 522 1  48 80 (gum) K 2.33 537 1  49 80 (gum) K 2.40 521 1  50 80(gum) K 2.84 498 1  51 80 (gum) K 3.22 484 1  52 80 (gum) K 3.29 500 1 53 n.d. — 2.99 443 1  54 80 (gum) K 2.81 475 1  55 80 (gum) K 3.45 5141  56  55 DSC 3.10 499 1  57 80 (gum) K 2.97 523 1  58 80 (gum) K 2.97523 1  59 n.d. — 2.69 473 1  60 n.d. — 2.69 473 1  61 n.d. — 2.69 473 1 62 >260  K 2.30 441 1  63 100 (gum)  K 2.77 510 1  64 80 (gum) K 3.02524 1  65 80 (gum) K 2.76 496 1  66 80 (gum) K 2.81 498 1  67 80 (gum) K2.27 537 1  68  49 DSC 2.89 425 1  69 80 (gum) K 3.28 551 1  70 80 (gum)K 2.88 498 1  71 80 (gum) K 2.77 484 1  72 80 (gum) K 2.60 497 1  73n.d. — 2.89 483 1  74 n.d. — 2.89 483 1  75 80 (gum) K 2.50 523 1  76 90 DSC 2.81 482 1  77 80 (gum) K 3.09 510 1  78 235 DSC 3.08 503 1  79n.d. — 2.14 483 1  80 244 DSC 3.18 429 1  81 n.d. — 2.62 485 1  82 n.d.— 5.81 511 3  83a 240 DSC 2.12 415 1  83b 180 DSC 2.10 Fragment m/z 1286 (weak 414.9)  83c 157 DSC 2.10 Fragment m/z 1 286 (weak 415.0)  8480 (gum) K 2.76 401 1  85 n.d. — 2.74 424 1  86  76 DSC 2.79 481 1  87 74 DSC 2.77 481 1  88 n.d. — 2.83 384 1  89 n.d. — 2.83 384 1  90 n.d.— 2.88 494 1  91 n.d. — 2.88 494 1  92 n.d. — 2.88 494 1  93 80 (gum) K2.92 497 1  94 80 (gum) K 2.71 496 1  95 80 (gum) K 2.73 496 1  96 80(gum) K 2.71 426 1  97 146 DSC 3.46 425 1  98 240 DSC 2.15 411 1  99 189DSC 3.33 445 1 100 n.d. — 2.66 383 1 101 80 (gum) K 2.99 484 1 102 80(gum) K 2.68 484 1 103 80 (gum) K 3.04 484 1 104 80 (gum) K 2.70 466 1105 161 DSC 2.92 480 1 106 80 (gum) K 3.74 411 1 107 80-90 (gum)    K3.74 411 1 111  80 K 2.91 397 1 112 80 (gum) K 3.46 498 1 113 307 DSC2.70 493 1 114 303 DSC 2.70 493 1 115 327 DSC 2.65 480 1 116 332 DSC2.64 480 1 117 n.d. — 2.44 440 1 117a 179 DSC 2.46 440 1 118 237 DSC2.44 440 1 118a n.d. — 2.45 440 1 119  80 K 2.84 482 1 120  80 K 2.76462 1 121  80 K 2.59 478 1 122 n.d. — 2.40 454 1 122a 116 DSC 2.31 454 1123 n.d. — 2.40 454 1 123a 130 DSC 2.34 454 1 124 80 (gum) K 2.88 526 1125 80 (gum) K 2.91 476 1 126 80 (gum) K 2.89 476 1 127 80 (gum) K 3.09434 1 128 80 (gum) K 3.09 434 1 129  80 K 2.63 528 1 130 159 DSC 2.50467 1 131  80 K 2.55 473 1 132 80 (gum) K 2.39 471 1 133 80 (gum) K 3.06516 2 134 80 (gum) K 2.28 508 2 135 144 DSC 2.90 423 1 136 184 DSC 2.67438 2 137 80 (gum) K 2.20 485 2 138 n.d. — 2.11 453 2 139 n.d. — 2.11453 2 140 80 (gum) K 2.86 454 2 141 80 (gum) K 2.86 454 2 142 80 (gum) K2.84 537 2 143 80 (gum) K 2.53 511 2 144 80 (gum) K 2.40 497 2 145 80(gum) K 2.30 472 2 146 80 (gum) K 2.92 Fragment m/z 1 355 (weak 500) 14780 (gum) K 2.56 487 1 148 n.d. — 2.68 544 1 149 80 (gum) K 2.40 501 1150 110 K 2.67 406 1 151 80 (gum) K 2.84 407 1 152 80 (gum) K 2.47 485 1153 90 (gum) K 2.73 372 1 154a n.d. — 2.76 401 1 154b  90 K 2.76 401 1155 186 DSC 2.58 431 1 156 n.d. — 2.88 Fragment m/z 1 383 (weak 518) 157n.d. — 2.88 Fragment m/z 1 383 (weak 518) 158 n.d. — 2.96 439 1 159 n.d.— 2.96 439 1 160 229 DSC 2.79 Fragment m/z 1 383 (weak 530) 161 228 DSC2.79 530 1 162 80 (gum) K 3.22 Fragments m/z 1 353 and 383 163 239 DSC3.21 Fragments m/z 1 353 and 383 164 116 DSC 3.05 Fragments m/z 1 335and 383 165 80 (gum) K 2.50 472 1 166 80 (gum) K 2.51 472 1 167 80 (gum)K 3.45 449 1 168 165 DSC 3.00 470 1 169 217 DSC 2.79 486 1 170 285 DSC2.15 Fragment m/z 1 286 (weak 433) 171 125 gum  K 3.12 565 + 1 fragmentm/z 436 172 130 gum  K 3.12 565 1 173 80 gum K 2.71 506 + 1 fragment m/z383 174 80 gum K 2.49 529 1 175 80 gum K 2.48 529 1 176 n.d. — 2.41525 + 1 fragment m/z 313 177 80 gum K 2.77 467 1 [M + Na]⁺ + fragmentm/z 316 178 80 gum K 2.77 467 1 [M + Na]⁺ + fragment m/z 316 180 148 K2.58 499 1 181 134 DSC 2.51 499 1 182 134 DSC 2.50 499 1 183 145 K 2.46485 1 184 157 DSC 2.42 485 1 184a 80° C. (gum)   K 2.54 485 1 184b 270DSC 2.57 485 1 184c  74 DSC 2.57 485 1 185 152 DSC 2.40 485 1 186 80(gum) K 3.18 468 1 187 80 (gum) K 3.18 468 1 188 80 (gum) K 2.52 458 + 1fragment m/z 329 189 80 (gum) K 2.52 458 + 1 fragment m/z 329 192 229DSC 3.00 512 + 1 fragment m/z 383 193 80 (gum) K 2.70 500 + 522 1 [M +Na]⁺ + fragment m/z 371 + 383 194 80 (gum) K 2.69 500 + 522 1 [M+Na]⁺ +fragments m/z 371 + 383 195 228 DSC 2.99 411 + 1 fragment m/z 383 196 80(gum) K 2.69 500 + 1 fragment m/z 383 197 80 (gum) K 2.68 500 + 1fragment m/z 383 198 171 DSC 2.61 459 1 199 140 K 2.50 459 1 200 115 gumK 2.50 459 1 201 2.61 472 1 202  70 DSC 2.61 472 1 203 118 DSC 2.75 4721 204 80 (gum) K 2.75 472 1 205 80 (gum) K 3.08 514 1 206 80 (gum) K3.27 498 1 207 80 (gum) K 3.09 514 1 208  80 K 3.28 498 1 209 183 DSC3.36 430 1 210  80 K 2.98 506 1 211 206 DSC 2.53 499 1 212 204 DSC 2.52499 1 213 80 (gum) K 2.58 476 1 214 80 (gum) K 2.58 476 1 217 n.d. —2.94 565 1 218 n.d. — 2.23 518 1 219 n.d. — 2.20 389 1 220 n.d. — 2.20389 1 222 163 DSC 2.98 506 1 223 200 DSC 2.76 526 1 224 163 DSC 2.66 5531 225 80 (gum) K 2.85 414 + 1 fragment m/z 285 226 158 DSC 2.39 481 1227 80 (gum) K 2.37 481 1 228 80 (gum) K 2.35 481 1 229 n.d. — 2.36 4441 230 218 DSC 2.27 426 1 231 n.d. — 2.61 490 1 232 181 DSC 2.46 458 1233 192 Kofler n.d. n.d. — 236 240 DSC 2.12 415 1 237  80 K 2.83 551 1237a 120 DSC 2.85 551 1 237b 120 DSC 2.84 551 1 237c  80 K 2.85 551 1237d  80 K 2.86 551 1 238 110 K 2.94 551 1 239 n.d. — 2.11 512 1 240n.d. — 2.10 512 1 241 n.d. — 2.10 512 1 242 n.d. — 2.12 512 1 243 n.d. —2.13 493 1 243a 160 K 2.10 493 1 243b 200 K 2.10 493 1 244 n.d. — 2.51484 1 245 n.d. — 2.50 484 1 246a n.d. — 2.56 472 1 246b  75 DSC 2.54 472Method 1 249 211 DSC n.d. n.d. — 250 120 K n.d. n.d. — 251 299 DSC n.d.n.d. — 262 222 DSC n.d. n.d. — 262a   199.7 DSC 3.10 411 1 262b   199.5DSC 3.10 411 1 264 189 DSC n.d. n.d. — 266 220 K n.d. n.d. — 276 194 DSC2.39 440 1 278 158 K 2.65 428 1 279  77 DSC 2.41 457 1 279a 80 (gum) K2.48 457 1 279b 80 (gum) K 2.48 457 1 280 164 DSC 2.44 471 1 280a 80(gum) K 2.51 471 1 280b 80 (gum) K 2.51 471 1 281 80 (gum) K 2.37 484 1281a 102 K 2.45 484 1 281b 80 (gum) K 2.44 484 1 282 100 (gum)  K 2.14452 1 282a 100 (gum)  K 2.33 452 1 282b 100 (gum)  K 2.34 452 1 283a 173DSC 2.51 516 1 283b 170 DSC 2.52 516 1 284a 113 K 2.66 489 1 284b 112 K2.66 489 1 286 85 (gum) K 2.61 499 1 286a 85 (gum) K 2.59 499 1 286b 85(gum) K 2.59 499 1 287 80 (gum) K 2.78 522 1 287a 90 (gum) K 2.78 522 1287b  95 K 2.78 522 1 292 80 (gum) K 2.74 503 1 292a 110 (gum)  K 2.74503 1 292b 110 (gum)  K 2.74 503 1 293 186 K 3.18 425 1 294 n.d. — n.d.n.d. — 295 80 (gum) K 2.55 453 1 295a 120 (gum)  K 2.56 453 1 295b 120(gum)  K 2.56 453 1 296 n.d. — 2.51 514 1 296a n.d. — 2.50 514 1 296bn.d. — 2.52 514 1 297 n.d. — 2.50 514 1 297a n.d. — 2.52 514 1 297b n.d.— 2.52 514 1 298a 100 (gum)  K 2.74 511 1 298b 100 (gum)  K 2.75 511 1299a 100 (gum)  K 2.55 485 1 299b 100 (gum)  K 2.55 485 1 300 n.d. n.d.2.48 483 1 300a 140 K 2.49 483 1 300b 135 K 2.49 483 1 301 315 DSC 2.44453 1 302  80 (GUM) K 2.61 497 1 302a 135 K 2.62 497 1 302b 135 K 2.62497 1 303 138 DSC 2.70 400 1 304 n.d. — 2.87 436 1 308 195 DSC 2.78 5391 309 n.d. — n.d. n.d. — 309a n.d. — 2.58 502 1 309b n.d. — 2.59 502 1312a n.d. — 2.75 515 1 312b n.d. — 2.75 515 1 313a n.d. — 2.86 515 1313b n.d. — 2.87 515 1 314a 80 (gum) K 2.55 481 1 314b 80 (gum) K 2.54481 1 315a 86 (gum) K 2.30 546 2 315b  90 K 2.29 547 1 317 167 DSC 1.92509 1 318 n.d. — 2.11 492 1 319a n.d. — 2.90 550 1 319b n.d. — 2.90 5501 320a 110 K 2.57 479 1 320b 136 K 2.58 479 1 321a 118 K 2.44 465 1 321b128 K 2.44 465 1 322a 122 K 2.40 496 1 322b  80 K 2.39 496 1 323a 126 K2.39 496 1 323b 130 K 2.41 496 1 324a  60 K 2.45 485 1 324b  60 K 2.45485 1 325a 144 K 2.39 482 1 325b 138 K 2.38 482 1 328  98 DSC 2.48 466 1329a 121 K 2.46 496 1 329b 124 K 2.46 496 1 332 169 DSC 2.75 427 1 333265 DSC 2.46 443 1 334a 136 DSC 2.50 441 1 334b 134 DSC 2.58 441 1 335an.d. — 2.55 503 1 335b 80 (gum) K 2.52 503 1 336 194 DSC 2.40 440 1 338n.d. — 2.43 454 1 338a   89.8 DSC 2.49 454 1 338b   90.8 DSC 2.49 454 1339 117 DSC 2.89 423 1 339a 131 DSC 2.97 423 1 339b 129 DSC 2.96 423 1340 180 DSC 2.19 457 1 341  80 K 2.89 429 1 342 n.d. — 2.31 485 1 343n.d. — 2.32 440 1 344a  75 K 2.36 472 1 344b  75 K 2.37 472 1 345a  80 K2.38 529 1 345b  80 K 2.38 529 1 346a 107 K 2.54 472 1 346b 106 K 2.54472 1 347 170 DSC 2.78 523 1 347a 125 K 2.80 523 1 347b 125 K 2.80 523 1348a 102 K 2.62 486 1 348b 102 K 2.62 486 1 349a  82 K 2.55 499 1 349b 82 K 2.55 499 1 351 n.d. — 2.22 483 1 352 n.d. — 2.25 483 1 353 80(gum) K 2.69 500 1 354 n.d. — 2.97 438 1 355 80 (gum) K 2.26 483 1 357a116 K 2.55 511 1 357b 120 K 2.55 511 1 358 80 (gum) K 2.86 442 1 359n.d. — 2.51 493 1 360 n.d. — 2.58 525 1 362 n.d. — 2.51 481 1 363a 80(gum) K 2.76 512 1 363b 80 (gum) K 2.75 512 1 364 80 (gum) K 2.50 499 1364a 80 (gum) K 2.47 499 1 364b 80 (gum) K 2.48 499 1 365 80 (gum) K2.39 497 1 365a 80 (gum) K 2.41 497 1 365b 80 (gum) K 2.40 497 1 366 154DSC 2.51 489 1 367a n.d. — 3.01 547 1 367b n.d. — 3.01 547 1 368 n.d. —2.26 483 1 369a n.d. — 2.99 524 1 369b 147 DSC 2.99 524 1 370a 128 DSC2.48 498 1 370b 80 (gum) K 2.50 498 1 371a 114 K 2.40 497 1 371b 107 K2.40 497 1 373 n.d. — 2.79 539 1 374a 132 K 2.36 483 1 374b 130 K 2.38483 1 375  80 K 2.99 524 1 376 130 gum  K 2.48 497 1 379a n.d. — 2.60504 1 379b n.d. — 2.59 504 1 380a n.d. — 2.59 488 1 380b n.d. — 2.60 4881 381 n.d. — 2.48 440 1 382 150 DSC 2.80 424 1 383 172 DSC 2.44 467 1384 n.d. — 2.36 471 1 385 n.d. — 2.50 495 1 386 n.d. — 2.65 509 1 388an.d. — 2.88 557 1 388b n.d. — 2.88 557 1 389 n.d. — 2.36 499 1 390 n.d.— 2.53 513 1 391 n.d. — 2.42 452 1 391a n.d. — 2.32 452 1 391b n.d. —2.32 452 1 392a 80 (gum) K 2.79 482 1 392b n.d. — 2.79 482 1 393a 115(gum)  K 1.99 454 1 393b 196 DSC 1.99 454 1 394 161 DSC 2.41 471 1 39580 (gum) K 2.97 468 1 395a 90 (gum) K 2.97 468 1 395b 102 K 2.97 468 1396 n.d. — 3.14 482 1 397 70 (gum) K 2.82 436 1 397a 80 (gum) K 2.83 4361 397b 80 (gum) K 2.83 436 1 398 n.d. — 3.10 465 1 399 202 K 2.96 474 1400 80 (gum) K 2.60 410 1 401 80 (gum) K 2.78 424 1 402 80 (gum) K 2.83442 1 403a  53 DSC 3.13 440 1 403b  54 DSC 3.13 440 1 404a n.d. — 2.60516 1 404b n.d. — 2.58 516 1 405a n.d. — 2.59 516 1 405b n.d. — 2.58 5161 406a 80 (gum) K 2.47 471 1 406b 80 (gum) K 2.47 471 1 407a 115 K 2.58481 1 407b 105 K 2.59 481 1 408a 127 DSC 2.47 444 1 408b 123 DSC 2.47444 1

OR data: Solvent: DMF; temperature: 20° C.; wavelength: 589 nm (‘Co.No.’ means Compound Number; ‘OR’ means optical rotation; ‘Conc.’ meansconcentration in g/100 mL)

Co. No. OR (°) Conc.  1 −292.75 0.392  2 +316.79 0.401  5 −412.51 0.331 6 +421.30 0.342  8 −382.23 0.266  9 +375.10 0.253  10 −402.40 0.258  12−414.74 0.285  13 +416.86 0.261  21 −320.83 0.264  22 +317.85 0.297  24−498.40 0.281  25 +527.65 0.327  31 +352.63 0.244  33 −295.09 0.265  34−239.57 0.278  37 +274.14 0.263  38 −238.83 0.291  40 −301.03 0.290  43+228.28 0.290  47 −243.13 0.276  51 −294.42 0.236  57 −213.58 0.202  58+231.82 0.220  60 +341.54 0.321  61 +421.30 0.342  73 −348.84 0.301  74+343.7 0.270  83b −513.10 0.229  83c −496.67 0.330  85 −363.50 0.194  88−459.09 0.264  89 +464.44 0.270  91 −348.27 0.245  92 +357.52 0.262 103−309.92 0.259 106 −432.69 0.260 107 +391.95 0.236 113 +308.69 0.224 114−337.35 0.191 117 −429.65 0.185 117a −342.13 0.254 118 +404.14 0.198118a +359.47 0.338 122 −3145.76 0.197 122a −314.81 0.216 123 +367.550.218 123a +317.06 0.293 127 −105.60 0.250 128 +107.53 0.242 137 −365.950.173 138 −373.79 0.237 139 +395.19 0.270 140 +73.81 0.279 141 +76.810.292 152 +335.71 0.280 154a −466.21 0.191 154b +480.87 0.274 156−317.47 0.256 157 +307.31 0.260 158 −249.76 0.208 159 +259.50 0.203 160−335.79 0.190 161 +318.44 0.242 162 −340.81 0.241 163 +292.77 0.188 165−370.38 0.260 166 +366.30 0.270 171 −313.87 0.252 172 +311.51 0.304 174+378.33 0.240 175 −335.27 0.258 177 −401.08 0.185 178 +427.32 0.194 181+295.85 0.265 182 −324.34 0.189 184 −376.8 0.250 185 +301.82 0.275 186−400.67 0.300 187 +402.33 0.314 188 −394.49 0.254 189 +420.35 0.226 192+285.27 0.258 195 −339.85 0.266 199 −350.00 0.260 200 +343.06 0.288 203−401.47 0.327 210 −334.15 0.244 211 −380.48 0.251 212 +360.74 0.298 213−393.33 0.315 214 +398.92 0.277 219 −341.38 0.290 220 +346.21 0.290 222+265.31 0.245 227 −372.39 0.268 228 +372.09 0.258 237a −335.17 0.290237b +319.70 0.264 243a −341.33 0.354 243b +375.76 0.445 244 +88.000.200 245 −67.62 0.245 249 −343.79 0.239 250 −374.62 0.231 251 −327.170.254 252 +352.63 0.244 257b +413.08 0.193 257c −367.10 0.207 262a−494.03 0.268 262b +483.66 0.257 279a −387.27 0.267 279b +401.56 0.256280a −358.62 0.290 280b 352.99 0.251 281a −353.28 0.259 281b +334.320.303 282a −373.79 0.237 282b +395.19 0.27 283a −347.53 0.324 283b+307.65 0.327 286a +308.51 0.282 286b −285.98 0.271 292a −342.13 0.224292b +354.32 0.238 295a −409.09 0.253 295b +409.72 0.288 296a −299.270.275 296b +264.91 0.285 297a +292.92 0.24 297b −303.53 0.238 298a−255.68 0.273 298b +391.81 0.293 299a −336.73 0.245 299b +316.61 0.289309a −344.58 0.249 309b +347.21 0.269 312a +400.77 0.26 312b −362.140.28 313a −316 0.25 313b +407.69 0.26 314a +346.67 0.255 314b −342.010.269 315a +285.04 0.274 315b −304.43 0.271 319a +6.84 0.263 319b −8.30.277 324a −303.6 0.25 324b +346.84 0.269 325a +334.04 0.285 325b −3760.25 329a −315.38 0.26 329b +321.85 0.27 334a −379.05 0.269 334b +344.920.305 335a −307.47 0.255 335b +302.73 0.33 339a −84.62 0.272 339b +87.020.222 344a −341.31 0.259 344b +325.98 0.254 345a −309.67 0.300 345b+313.61 0.294 348a −301.71 0.297 348b +358.89 0.253 349a −330.45 0.312349b +322.3 0.287 352 +18.94 0.396 355 +25.61 0.285 357a +350.18 0.285357b −342.9 0.331 359 −16.73 0.269 363a −376.21 0.269 363b +260.7 0.57367a +5.62 0.267 367b −9.6 0.267 368 −40.22 0.271 369a −333.22 0.304369b +146.67 0.266 370a −333.42 0.304 370b +340.23 0.266 374a −294.400.25 374b +376.33 0.3 379a −353.65 0.274 379b +316.25 0.277 380a +381.390.274 380b −401.88 0.266 388a +279.3 0.256 388b −273.06 0.271 391a−287.94 0.257 391b −301.54 0.260 392a −384.21 0.248 393a −381.05 0.281393b +315.51 0.245 395a −142.92 0.365 395b +171.98 0.335 397a +33.210.268 397b −35.66 0.258 398 −120.03 0.319 403a −246.42 0.723 403b+236.25 0.245 404a +302.98 0.235 404b −327.05 0.233 405a +341.45 0.226405b −329.15 0.223 406a −390.85 0.308 406b +394.78 0.287 407a −356 0.25407b +347.54 0.242 408a −400.66 0.302 408b +390.38 0.312

SFC-MS Methods:

General Procedure for SFC-MS Methods

The SFC measurement was performed using an Analytical Supercriticalfluid chromatography (SFC) system composed by a binary pump fordelivering carbon dioxide (CO₂) and modifier, an autosampler, a columnoven, a diode array detector equipped with a high-pressure flow cellstanding up to 400 bars. If configured with a Mass Spectrometer (MS) theflow from the column was brought to the (MS). It is within the knowledgeof the skilled person to set the tune parameters (e.g. scanning range,dwell time . . . ) in order to obtain ions allowing the identificationof the compound's nominal monoisotopic molecular weight (MW). Dataacquisition was performed with appropriate software.

TABLE Analytical SFC-MS Methods (Flow expressed in mL/min; columntemperature (T) in ° C.; Run time in minutes, Backpressure (BPR) inbars). Method Flow Run time number column mobile phase gradient Col TBPR 1 Daicel Chiralpak ® A: CO₂ 25% B 3 7 AD-H column (5 μm, B:EtOH(+0.3% hold 7 min, 35 100 150 × 4.6 mm) iPrNH₂) 2 Daicel Chiralpak ®A: CO₂ 30% B 3 7 AD-H column (5 μm, B: EtOH(+0.3% hold 7 min, 35 100 150× 4.6 mm) iPrNH₂) 3 Daicel Chiralpak ® A: CO₂ 40% B 3 7 AD-H column (5μm, B: EtOH(+0.3% hold 7 min, 35 100 150 × 4.6 mm) iPrNH₂) 4 DaicelChiralpakl ® A: CO2 20% B 3.5 3 AS-3 column (3 μm, B: EtOH(+0.3% hold 3min, 35 103 100 × 4.6 mm) iPrNH2) 5 Daicel Chiralpakl ® A: CO2 25% B 3.53 AS-3 column (3 μm, B: MeOH(+0.3% hold 3 min, 35 103 100 × 4.6 mm)iPrNH2) 6 Daicel Chiralcel ® A: CO₂ 15% B 3 7 OJ-H column (5 μm, B:EtOH(+0.3% hold 7 min, 35 100 150 × 4.6 mm) iPrNH₂) 7 Daicel Chiralcel ®A: CO₂ 25% B 3 7 OJ-H column (5 μm, B: EtOH(+0.3% hold 7 min, 35 100 150× 4.6 mm) iPrNH₂) 8 Daicel Chiralcel ® A: CO₂ 20% B 3 7 OJ-H column (5μm, B: MeOH(+0.3% hold 7 min, 35 100 150 × 4.6 mm) iPrNH₂) 9 DaicelChiralcel ® A: CO₂ 25% B 3 7 OJ-H column (5 μm, B: MeOH(+0.3% hold 7min, 35 100 150 × 4.6 mm) iPrNH₂) 10 Daicel Chiralpakl ® A: CO₂ 25% B3.5 3 AD-3 column (3 μm, B: EtOH(+0.3% hold 3 min, 35 103 100 × 4.6 mm)iPrNH₂) 11 Daicel Chiralpakl ® A: CO₂ 40% B 3.5 3 AD-3 column (3 μm, B:EtOH(+0.3% hold 3 min, 35 103 100 × 4.6 mm) iPrNH₂)

TABLE Analytical SFC-MS data - R_(t) means retention time (in minutes),method refers to the method used for (SFC)MS analysis ofenantiomerically pure compounds. Chiral purity Method Co. No. Rt UV Area% number 237c 1.43 100 9 237d 1.78 99.69 9 364a 0.79 100 11 364b 2.00100 11 365a 5.31 100 2 365b 6.44 100 2 392b 3.96 100 3 207* 2.42 55 6208 1.65 100 8 371a 2.14 100 1 371b 2.6 99.48 1 322a 1.41 99.46 5 322b1.81 99.33 5 323a 1.32 97.97 5 323b 1.77 99.09 5 201 1.87 100 8 202 2.84100 8 205 3.71 45 6 284a 1.56 100 7 284b 1.96 99.46 7 338a 2.16 100 7338b 2.7 99.44 7 287a 1.61 100 10 287b 1.96 95.36 10 201 2.08 100 8 2023.07 100 8 347a 5.02 100 1 347b 4.48 100 1 302a 1.43 100 4 302b 1.89 1004 300a 3.24 100 2 300b 4.73 100 2 *Co. No. 207 is a mixture of 2diastereoisomers

¹H NMR (500 MHz, DMSO-d₆) 5 ppm 9.44 (s, 1H) 7.94 (d, J=1.9 Hz, 1H) 7.75(d, 0.7=1.6 Hz, 1H) 7.32 (br s, 1H) 7.06 (d, J=7.9 Hz, 1H) 6.12-6.24 (m,1H) 6.06-6.12 (m, 2H) 5.66 (quin, J=6.9 Hz, 1H) 4.40 (q, J=2.5 Hz, 2H)3.93 (t, J=5.5 Hz, 2H) 3.01 (s, 3H) 2.74-2.88 (m, 5H) 1.56 (d, J=6.9 Hz,3H)

Compound 14 ¹H NMR data:

Compound 117: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.93 (s, 1H) 8.55 (t,J=5.5 Hz, 1H) 8.27 (d, J=2.2 Hz, 1H) 8.11 (d, J=2.2 Hz, 1H) 6.88-6.98(m, 1H) 6.70 (d, J=7.3 Hz, 1H) 6.24-6.32 (m, 1H) 6.14-6.23 (m, 2H) 5.44(quin, J=6.8 Hz, 1H) 4.72 (t, 0.7=5.7 Hz, 1H) 3.73-3.88 (m, 8H) 3.51 (q,J=6.0 Hz, 2H) 3.28-3.33 (m, 2H) 1.49 (d, J=6.6 Hz, 3H)

Compound 184: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.93 (s, 1H) 8.49 (t,J=5.5 Hz, 1H) 8.25 (d, J=1.9 Hz, 1H) 8.08 (d, J=1.9 Hz, 1H) 7.02 (d,J=7.3 Hz, 1H) 5.98-6.18 (m, 3H) 5.44 (q, J=6.8 Hz, 1H) 3.73-3.90 (m, 8H)3.36 (q, J=6.6 Hz, 2H) 2.40 (t, 0.7=6.8 Hz, 2H) 2.17 (s, 6H) 1.49 (d,J=6.9 Hz, 3H)

Compound 276: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.85 (s, 1H) 8.38 (br t,J=5.4 Hz, 1H) 7.61 (d, J=1.3 Hz, 1H) 7.09-7.18 (m, 1H) 6.96-7.08 (m, 2H)6.90 (d, J=0.9 Hz, 1H) 6.76 (br t, J=6.1 Hz, 1H) 4.70 (t, J=5.7 Hz, 1H)4.55 (br d, J=6.3 Hz, 2H) 3.73-3.88 (m, 8H) 3.48 (q, J=6.0 Hz, 2H) 3.29(q, J=6.2 Hz, 2H) 2.29 (s, 3H)

Compound 158: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.86 (s, 1H) 7.69 (s, 1H)7.23 (d, J=1.3 Hz, 1H) 6.25 (br t, J=9.5 Hz, 1H) 5.97 (br d, J=10.4 Hz,2H) 5.61 (br d, 0.7=7.6 Hz, 1H) 4.46 (br s, 1H) 3.70-3.86 (m, 11H)3.36-3.46 (m, 3H) 2.44-2.50 (m, 1H) 1.81-2.09 (m, 3H)

Compound 12: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.91 (s, 1H) 7.74 (d, J=1.9Hz, 1H) 7.59 (d, J=1.9 Hz, 1H) 6.99 (d, J=7.6 Hz, 1H) 6.14 (tt, J=9.5,2.2 Hz, 1H) 6.04-6.09 (m, 2H) 5.44 (quin, J=6.9 Hz, 1H) 3.75-3.89 (m,8H) 2.74-3.09 (m, 6H) 1.50 (d, J=6.6 Hz, 3H)

Compound 39: ¹H NMR (400 MHz, DMSO-d₆) 5 ppm 8.92 (s, 1H) 7.72 (s, 1H)7.06 (br s, 1H) 6.26 (br t, J=9.6 Hz, 1H) 5.97 (br d, J=10.1 Hz, 2H)5.58 (d, J=8.1 Hz, 1H) 4.27 (br s, 1H) 3.64-3.98 (m, 9H) 3.40 (br q,J=7.6 Hz, 1H) 3.15 (br s, 1H) 2.60 (br s, 2H) 2.10-2.44 (m, 4H)1.77-2.07 (m, 3H) 0.39-1.10 (m, 6H).

Compound 211: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.94 (s, 1H) 8.55 (t,J=5.1 Hz, 1H) 8.27 (d, J=1.9 Hz, 1H) 8.08 (d, J=1.9 Hz, 1H) 7.07 (d,J=7.3 Hz, 1H) 6.12 (tt, 0.7=9.5, 2.0 Hz, 1H) 6.06 (br d, J=11.0 Hz, 2H)5.44 (quin, J=6.8 Hz, 1H) 3.72-3.92 (m, 8H) 3.28-3.32 (m, 2H, partiallyobscured by solvent peak) 2.61-2.78 (m, 3H) 1.61 (br s, 1H) 1.49 (d,J=6.6 Hz, 3H) 0.96 (d, J=6.0 Hz, 6H)

Compound 328: ¹H NMR (500 MHz, DMSO-d₆) 5 ppm 8.93 (s, 1H) 8.50 (br t,J=5.5 Hz, 1H) 8.25 (s, 1H) 8.01 (s, 1H) 6.85 (q, J=7.9 Hz, 1H) 6.32 (t,J=9.0 Hz, 1H) 6.18 (d, 0.7=8.2 Hz, 1H) 5.99 (br t, J=6.0 Hz, 1H) 4.80(br d, J=5.7 Hz, 2H) 3.71-3.94 (m, 8H) 3.34-3.37 (m, 2H, partiallyobscured by solvent peak) 2.39 (br t, J=6.9 Hz, 2H) 2.16 (s, 6H) 2.09(s, 3H)

Pharmacology Update

Enzyme Binding Assays (KINOMEscan®)

Kinase enzyme binding affinities of compounds disclosed herein weredetermined using the KINOMEscan technology performed by DiscoveRxCorporation, San Diego, Calif., USA (www.kinomescan.com). Table Areports the obtained Kd values (nM), with the Kd being the inhibitorbinding constant:

Kd Kd Kd Kd Kd PIK3Cα_h PIK3Cβ_h PIK3Cδ_h PIK3Cγ_h MTOR_h Co. No. (nM)(nM) (nM) (nM) (nM)  1 34 0.3 15 313 28184  2 12276 108616407 >30200 >30200  3 47 1 20 229 17783  4 23442 169822909 >30200 >30200  5 1587 2 225 7977 25119  6 26003 189416923 >30200 >30200  7 513 2 245 10000 >30200  8 396 1 109 3864 20893  927542 417 18197 >30200 >30200  10 142 0.5 74 336 >30200  11 631 1 2752512 >30200  12 276 0.4 75 1137 26331  13 23855 182 5888 >30200 >30200 14 174 0.2 36 229 >10000  15 234 1 43 372 >30200  16 93 1 16 126 16982 17 25 0.1 3 107 12303  18 5 0.1 1 37 21878  19 363 0.2 29 309 18197  203631 17 1549 22387 21878  21 4786 63 2239 15849 19953  22 15136 562318621 >30200 21878  23 324 1 331 724 15136  24 302 1 245 372 18621  2512303 37 4677 12883 >30200  26 174 2 117 1318 >30200  27 269 1 581622 >30200  28 107 1 29 832 >30200  29 10233 1660 21878 >30200 23442 30 39 1 18 407 21878  31 >32000 >32000 >32000 >32000 >32000  32 120 185 646 >30200  33 58 1 47 389 >30200  34 50 0.4 30 933 >30200  35 162 2151 1905 >30200  36 224 2 107 1585 15849  37 6166 20 2884 >30200 >30200 38 3 0.4 6 933 >30200  39 14 0.2 7 214 >30200  40 56 1 35 309 17378  41389 1 141 1380 >30200  42 331 1 56 1479 >30200  43 4677 316 72441096 >30200  44 234 1 174 631 23442  45 170 3 126 2089 31623  46 9333 859550 >30200 >30200  47 41 0.2 32 759 14791  48 2455 28 724 14791 >30200 49 2188 16 933 7586 >30200  50 11 0.2 8 87 8913  51 55 1 39 339 >30200 52 6166 38 4898 13804 >30200  53 2951 3 692 21380 >30200  54 16218 1157079 >30200 26915  55 >30200 3981 >30200 >30200 >30200  56 6607 132630 >30200 >30200  57 49 0.4 31 525 25119  58 1995 9 912 18621 >30200 59 1202 3 331 10715 >30200  60 22909 490 15488 >30200 >30200  61 676 2209 5248 >30200  62 25 1 51 234 2042  63 79 0.5 27 891 8128  64 224 1 581288 15136  65 38 1 17 200 10715  66 65 2 79 676 16982  67 2455 18 61720893 >30200  68 3162 3 589 15136 22387  69 891 3 195 3090 >30200  70339 2 148 1096 19055  71 251 1 138 794 22387  72 56 0.2 17 204 20417  732042 9 282 19498 >30200  74 8511 603 5623 >30200 23442  75 30 0.1 24 >30200  76 50 0.1 19 251 >30200  77 363 0.3 100 646 >30200  78 3715 151175 13490 >30200  79 2291 2 204 19953 >30200  80 >30200 50 758624547 >30200  81 19055 30 2630 29512 >30200  82 12303 15166 >30200 >30200  84 692 1 96 1288 8511  85 257 0.3 41 1660 562  863467 15 537 21380 >30200  87 22909 1380 9550 >30200 >30200  88 2138 5603 4677 14125  89 7244 832 11749 9550 13490  90 9120 17 74122909 >30200  91 4467 10 1230 21380 >30200  92 16218 102316596 >30200 >30200  93 219 0.3 33 191 21878  94 79 0.1 29 178 21380  95295 0.5 178 1096 >30200  96 363 0.4 83 302 17378  97 19055214 >30200 >30200 >30200  98 479 47 955 437 2239  99 9772 52 467711482 >30200 100 1288 1 295 1738 14125 101 263 0.4 40 398 >30200 102 2450.2 31 398 >30200 103 1134 3 1001 2995 24547 104 1349 3 263 17783 >30200105 3890 8 871 28184 >30200 106 3162 6 1000 3311 >30200 107 >30200 36323442 >30200 >30200 111 6026 16 1820 1479 10000 112 955 1 2042399 >30200 113 >30200 1023 >30200 >10000 >30200 114 1622 1 1866918 >30200 115 1660 2 324 10000 >30200 116 >30200 288430200 >30200 >30200 117 1105 3 324 3412 17128 118 14232 204 101922851 >30200 119 2239 2 490 11749 >30200 120 6761 14 2188 >30200 >30200121 5370 10 1585 >30200 >30200 122 2884 0.3 151 5623 25704 123 9333 912239 12589 16596 124 1072 4 575 7762 8128 125 6457 68 5888 >30200 >30200126 6918 13 1288 >30200 >30200 127 6457 32 2291 21878 25704 128 48981122 15136 12303 21380 129 1778 3 1072 8913 9772 130 363 0.5 135 2406166 131 3162 11 2512 19953 >30200 132 832 0.5 115 2188 11482 133 5754 3263 26303 >30200 134 >30200 87 6310 >30200 >30200 135 10000 195 380217378 11220 136 2344 3 355 5129 15136 137 138 0.1 9 501 >30200 138 3980.1 56 2150 30903 139 3765 41 4423 3433 18621 140 14791 5129 1584925119 >30200 141 6607 6 776 8128 >30200 142 209 0.5 59 741 >30200 1432818 2 389 9550 >30200 144 1738 2 437 5623 >30200 145 537 1 102 186223442 146 1905 2 933 8128 >30200 147 776 0.4 129 1148 >30200 148 1072 1316 8128 >30200 149 2951 2 398 2344 >30200 150 2884 3 501 3715 >30200151 3631 8 813 8710 >30200 152 3981 10 1820 8710 >30200 153 5370 8 11752692 16218 155 2138 6 759 6607 >30200 156 398 2 363 >30200 >30200 15713183 102 19953 >30200 >30200 158 339 0.4 120 2291 >30200 159 >30200 11023442 >30200 >30200 160 813 2 575 9772 19498 161 >30200776 >30200 >30200 >30200 162 3981 9 1230 24547 >30200 163 >30200 83216218 >30200 >30200 164 2399 4 1096 13804 >30200 165 1778 0.3 182 549514125 166 16596 19 4074 14791 21878 167 17378 26 7762 12883 >30200 1683631 17 1862 >30200 >30200 169 4074 8 1122 5370 18621 170 617 5 288 22394365 171 2188 3 575 >30200 >30200 172 >30200 1259 >30200 >30200 >30200173 832 1 372 3548 24547 174 >30200 1202 26303 >30200 >30200 175 16980.4 112 2570 >30200 176 1995 1 102 3467 >30200 177 1380 2 170 6918 23988178 >30200 1096 16596 >30200 >30200 180 891 0.1 49 2188 >30200 181 5012117 20417 17783 >30200 182 126 0.3 32 912 >30200 183 2512 0.1 1021738 >30200 184 599 0.2 57 994 18905 185 5754 29 5370 4266 >30200 1866310 10 1778 27542 >30200 187 >30200 1047 >30200 >30200 >30200 188 851 1182 2291 16218 189 >30200 2512 28184 4467 >30200 192 >302009120 >30200 >30200 >30200 193 >30200 158 17783 >30200 >30200 194 >302001820 >30200 >30200 >30200 195 1950 2 479 12883 >30200 196 2818 5 81315849 >30200 197 692 3 302 13804 >30200 198 11220 22 3162 15488 >30200199 4898 68 5495 11749 28840 200 >30200 2399 >30200 >30200 >30200 2011455 2 710 4451 16549 202 >30200 3948 >30200 3325 6026 203 1660 5 9126607 21380 204 >30200 1072 >30200 14454 >30200 205 >30200 20417378 >30200 >30200 206 >30200 7079 >30200 >30200 >30200 207 5248 6 89116218 7943 208 3467 8 1413 >30200 >30200 209 >30200 316 1148216982 >30200 210 3162 12 1023 >30200 >30200 211 3369 1 190 3599 20198212 7093 12 3291 5073 13804 213 2089 2 269 3236 7762 214 >302001230 >30200 4571 >30200 217 2138 4 1288 23988 >30200 218 537 5 1175 30903311 219 93 1 275 955 3311 220 25704 2754 >30200 25704 6457 222 >30200759 >30200 >30200 >30200 223 >30200 4786 >30200 13804 >30200 224 27542186 4467 >30200 >30200 225 4677 6 537 2512 >30200 226 2570 1 275 562328840 227 1778 1 339 3802 >30200 228 6166 603 15488 4074 >30200 229 38907 1738 20417 12589 230 7079 12 759 18197 12023 231 1698252 >3311 >30200 >10000 232 16218 98 2818 >30200 13183 234 n.d. n.d. n.d.n.d. n.d. 235 >32000 50 7586 24547 >32000 236 112 2 158 813 1318 237 2881 138 9333 >30200 238 5013 8 2211 12306 >30200 239 603 2 316 1288 10471240 9333 2239 17378 18197 >30200 241 427 8 589 5370 22387 242 15849 478617783 >30200 >30200 243 66 1 71 145 1905 244 8318 741 4169 12589 19953245 8710 72 1047 13183 21878 249 794 4 955 2399 >30200 250 339 1 219 95514454 251 8 0.3 23 65 676 252 >30200 >30200 >30200 >30200 >30200 262n.d. n.d. n.d. n.d. n.d. 264 9772 52 4677 11482 >30200 272 4898 51995 >30200 >30200 273 6310 8 2754 >10000 >30200 276 1950 4 871 912010965 278 2089 8 1738 15849 19498 279 5370 5 372 6457 19055 280 5129 6427 11220 >30200 281 3162 0.3 91 3548 >30200 282 832 0.2 68 1820 23442286 7413 18 2042 16982 >30200 287 2692 13 977 26303 >30200 291 550 4072818 513 10233 292 6607 16 1698 27542 >30200293 >30200 >30200 >30200 >30200 >30200 295 7244 309 7762 6310 30903 2962951 1 166 6457 >30200 297 1862 0.3 110 1950 >30200 300 2692 4 51316982 >30200 301 5370 43 3236 1514 15136 302 1950 5 380 15488 >30200 3033548 9 457 3890 18621 304 7244 62 6761 19953 >30200 308 >30200 3247244 >30200 >30200 309 n.d. n.d. n.d. n.d. n.d. 316 12883 211380 >30200 >30200 317 6166 13 708 20893 >30200 318 3467 6288 >30200 >30200 328 1905 0.2 324 6607 17783 332 2951 15 426621380 >30200 333 5248 37 7413 17378 >30200 336 1950 4 871 9120 10965 3373981 35 3802 7943 >30200 338 2344 12 2951 4365 >30200 339 5888 427 24559333 16218 340 1514 2 372 5012 12023 341 3388 17 1479 8128 21380 3423802 9 1000 26915 16596 343 2188 22 3311 10000 >10000 347 3715 4 40728840 >30200 350 n.d. n.d. n.d. n.d. n.d. 351 2512 21 1698 2138 >30200352 2291 2 1000 9772 >30200 353 5012 4 692 >30200 >30200 354 8128 632399 28184 >30200 355 4786 13 2884 20893 13183 358 10000 148 223917783 >30200 359 11327 43 796 28840 6463 360 6761 42 11749 26915 >30200361 2951 2 490 9772 19055 362 2951 2 490 9772 19055 364 7413 5 81313804 >30200 365 2089 1 117 2884 >30200 366 1047 4 123 1318 4266 3685370 7 1413 >30200 >30200 373 >30200 158 5248 >30200 >30200 375 18621117 2188 >30200 >30200 376 4266 1 295 5129 >30200 381 3548 26 38028318 >30200 382 >30200 17 5012 >30200 >30200 383 1230 1 234 7943 7079384 2692 1 575 15849 19953 385 933 1 347 6166 16596 386 3236 15 69214791 24547 389 3162 5 2188 >30200 >30200 390 16596 78 3236 22387 >30200391 5495 251 3388 12023 24547 394 3236 0.2 776 12589 23442 395 3467 332239 14125 18197 396 7762 120 2042 20893 >30200 397 2692 36 66122909 >30200 398 10715 257 5754 >30200 >30200 399 2818 45 52489333 >30200 400 2344 24 1585 18621 26303 401 1862 550 12303 >30200 11482402 4467 44 4074 >30200 >30200 117a n.d. n.d. n.d. n.d. n.d. 118a n.d.n.d. n.d. n.d. n.d. 122a 3702 3 660 7969 14125 123a 10233 107 5129 1148216982 154a 437 1 98 741 8511 154b 20893 490 14791 7762 25119 184a 8060.1 74 1483 21880 184b 589 0.1 66 1096 19953 184c 829 0.1 54 1268 23988237a 105 1 204 5012 >30200 237b 8710 74 7762 >30200 >30200 237c 372 4234 5495 >30200 237d 12589 240 19498 >30200 >30200 243a 39 0.5 69 1001479 243b 1660 14 3388 1950 1349 246a 813 4 3890 6761 26915 246b >3020016596 >30200 6166 >30200 257b 851 22 468 3090 2818 257c 1698 603 30203162 1660 262a >30200 1778 24547 >30200 >30200 262b >3020011482 >30200 >30200 >30200 279a 2188 7 513 5623 21380 279b 26303 190530200 6457 >30200 280a 1698 12 562 12023 20893 280b 22387 813 2138024547 >30200 281a 1514 0.3 72 4074 23442 281b 6166 151 3467 7413 >30200283a 12023 7 1549 19055 >30200 283b >30200 1380 18197 29512 >30200 284a2076 10 939 8137 19055 284b >30200 2145 >30200 5070 >30200 286a 10233182 5754 >30200 25704 286b 6026 2 355 16218 >30200 287a 1738 3 23420893 >30200 287b 9333 27 2951 >30200 >30200 292a 2818 17 603 2187832359 292b >30200 14791 >30200 >30200 >30200 295a 6457 288 6761 >3020014454 295b >30200 19498 >30200 4571 >30200 296a 1380 1 170 3236 >30200296b >30200 14 9333 >30200 >30200 297a 16982 26 6310 15136 >30200 297b1023 0.5 112 1479 >30200 298a 4786 4 724 24547 >30200 298b 23988 18610233 >30200 >30200 299a 6310 1 269 10965 >30200 299b 13183 60 524819498 >30200 300a 1479 2 191 5495 >30200 300b 23988 53723442 >30200 >30200 302a >30200 1318 >30200 >30200 >30200 302b 1096 3186 11749 >30200 309a 1096 0.1 59 1738 19953 309b 4898 18 23445623 >30200 312a 15488 1148 10000 >30200 >10000 312b 5129 26 1862 2818419953 313a 5012 3 851 26303 >30200 313b 14454 302 5495 >30200 >30200314a 17378 417 6026 30200 19055 314b 8913 2 1000 16596 >30200315a >30200 2239 >30200 >30200 >30200 315b 2754 1 162 5495 >30200 319a9120 200 2818 >30200 >30200 319b 4365 59 1023 >30200 >30200 320a 513 2182 4467 >30200 320b 11482 69 5129 >30200 >30200 321a 832 1 1744677 >30200 321b 18621 166 7413 >30200 >30200 322a 29512 51323988 >30200 >30200 322b 2188 0.3 68 6166 >30200 323a >30200 100028840 >30200 >30200 323b 3802 1 182 3090 >30200 324a 1738 0.5 837244 >30200 324b 4898 229 3090 22387 >30200 325a 10715 1318 1148214125 >30200 325b 3020 4 525 12023 9120 329a 339 0.1 26 2754 22909 329b6026 42 1778 6310 22909 334a 5370 19 1072 12883 26915 334b 21380 4577586 10965 17378 335a 466 0.2 33 1218 18621 335b 8315 11 342113490 >30200 338a 1514 11 1072 7244 25704 338b 22909 851 >30200 234419953 339a 4571 112 2089 10715 >30200 339b 759 316 1950 2188 6457 344a2138 2 288 8318 >30200 344b 8128 166 3802 14125 >30200 345a 4365 2 28214791 >30200 345b >30200 724 22909 >30200 >30200 346a 2512 3 955 955030903 346b 23442 741 20893 2754 >30200 347a >302002692 >30200 >30200 >30200 347b 3890 2 355 25704 >30200 348a 3020 10 91229512 >30200 348b >30200 1318 25704 >30200 >30200 349a 813 0.2 364266 >30200 349b 4677 14 2754 25704 >30200 356a n.d. n.d. n.d. n.d. n.d.356b n.d. n.d. n.d. n.d. n.d. 357a 22909 3311 16218 >30200 >30200 357b933 1 158 8128 >30200 363a 10965 10 417 26915 >30200 363b 31623 128816982 >30200 27542 364a 2455 1 204 6918 >30200 364b 7079 372 77628128 >30200 365a 5248 1 204 10233 >30200 365b 15488 251 416922909 >30200 367a 4074 63 1148 23442 29512 367b 2455 35 427 >30200 28184369a 7244 20 525 >30200 25119 369b >30200 3311 28840 >30200 >30200 370a1230 0.3 107 2630 >30200 370b >30200 550 15488 >30200 >30200 371a 15140.3 83 1047 >30200 371b 12589 20 5012 10965 >30200 374a 2455 0.3 1415888 >30200 374b 13490 98 5754 21878 >30200 379a 9772 2813 >30200 >30200 379b >30200 1259 >30200 >30200 >30200 380a 9120 10477244 10000 19055 380b 3802 5 1202 8913 18621 388a >30200933 >30200 >30200 >30200 388b 2188 3 200 2399 >30200 391a >3020010715 >30200 >30200 16982 391b >30200 19498 >30200 >30200 >30200 392a3981 21 2818 14125 20417 392b n.d. n.d. n.d. n.d. n.d. 393a 437 11 12301380 6761 393b 10965 2291 25704 6607 15849 395a 3467 33 125917783 >30200 395b 3981 631 3548 32359 18621 397a 3631 1413 10715 2511915488 397b 1862 25 871 12303 >30200 403a 1479 3 331 8913 >30200403b >30200 3162 17378 >30200 >30200 404a >302001514 >30200 >30200 >30200 404b 5248 1 1072 16596 >30200 405a >30200 5017413 >30200 >30200 405b 5012 1 219 4677 20893 406a 372 0.1 39 1047 22909406b 7413 141 3467 3802 >30200 407a 2042 7 724 7943 10471 407b 4365 3392951 3802 >30200 408a 1445 3 331 4266 26303 408b 23442 324 173788128 >30200  83a 112 2 158 813 1318  83b 170 1 129 562 1288  83c 3090158 4898 2692 3090

Cellular Assays:

Cellular activity of PI3Kβ inhibitors was determined by quantifying thephosphorylation of Akt in PC-3 cells. Akt phosphorylated at Ser473 andThr308 were measured using an enzyme-linked immunosorbent assay (ELISA;Meso Scale Discovery (MSD), Gaithersburg, Md.) and specific primaryantibodies from MSD.

On day 1, PC3 cells (ATCC #CRL-14351) were seeded into PerkinElmer MW96plates at 25.000 cells per well, in 75 μl complete culture medium (DMEMhigh glucose, AQmedia™, D0819, Sigma-Aldrich) containing 10% heatinactivated PCS and incubated at 37° C., 5% CO2 during 24 hours. On day2, compound or DMSO (0.3%) was added and cells were further incubatedfor 60 min at 37° C. 5% CO2 in a total volume of 100 μl of medium.

The phosphoprotein assay was executed according to vendor instructionsin the Phospho-Akt (Ser473) Assay Whole Cell Lysate Kit (MSD #K15100D-3)and the Phospho-Akt (Thr308) Assay Whole Cell Lysate Kit (MSD#K151DYD-3) using the lysis, blocking and wash buffer provided.

Briefly, at the end of the cell treatment period, media were removed byaspiration and adherent cells were lysed in 50 μl ice-cold lysis buffer.MSD plates are supplied pre-coated with capture antibodies forPhospho-Akt (Ser473 and Thr308). After blocking, lysates from tissueculture plates were added and plates were washed. Then, a solutioncontaining the detection antibody (anti-total Akt conjugated with anelectrochemiluminescent compound-MSD Sulfo-tag label) was added. Thesignals were detected using an MSB SECTOR Imager 6000 and areproportional to the phospho-Akt titres.

Data were processed. The percentage of inhibition was plotted againstthe log concentration of test compounds, and the sigmoidal logconcentration-effect curve of best fit was calculated by nonlinearregression analysis. From these concentration-response curves, the IC₅₀values were calculated. Five concentrations were used for curve fitting.

Table B reports the obtained IC₅₀ values (nM): IC₅₀ pAkt_S473 IC₅₀pAkt_Thr308 Co. No. (nM) (nM)  1 2 3  2 >513 >513  3 3 ~3  4 >513 >513 5 100 99  6 >513 >513  7 42 21  8 25 20  9 >513 >513  10 4 3  11 81 42 12 18 9  13 >513 >513  14 31 11  15 4 2  16 ~5 2  17 ~3 1  18 1 0.3  1915 10  20 363 372  21 513 ~501  22 >513 >513  23 ~68 42  24 36 30 25 >513 >513  26 4 ~1.35  27 22 14  28 5 6  29 >513 >513  30 5 ~4 31 >513 >513  32 12 17  33 3 4  34 <0.8 3  35 ~39 ~26.92  36 10 5  37200 126  38 ~0.8 1  39 7 5  40 7 4  41 31 22  42 16 11  43 >513 331  4474 66  45 166 72  46 >513 >513  47 3 4  48 >513 ~457  49 >513 468  50 11  51 3 3  52 >513 240  53 214 148  54 >513 >513  55 >513 >513  56 >513148  57 ~5 4  58 >513 295  59 263 110  60 >513 >513  61 182 123  62 5232  63 9 4  64 13 6  65 6 2  66 13 6  67 195 166  68 257 148  69 117 ~32 70 ~45 23  71 ~15 13  72 2 1  73 >513 331  74 >513 >513  75 2 1  76 7 7 77 ~76 ~51  78 ~219 ~295  79 158 123  80 ~214 ~79  81 ~490 219 82 >513 >513  84 56 32  85 48 78  86 513 263  87 >513 >513  88 178 89 89 >513 >513  90 >513 >513  91 >513 234  92 >513 >513  93 41 28  94 812  95 34 18  96 25 20  97 >513 >513  98 >513 >513  99 >513 355 100 14568 101 21 14 102 22 23 103 65 28 104 110 55 105 302 138 106 105 62107 >513 >513 111 389 162 112 174 ~62 113 >513 >513 114 50 18 115 66 31116 >513 >513 117 49 44 118 >513 >513 119 105 81 120 479 269 121 347~331 122 40 26 123 >513 >513 124 151 93 125 >513 >513 126 427 275 127~457 331 128 >513 >513 129 112 105 130 89 65 131 501 363 132 52 37 13359 32 134 >513 >513 135 >513 >513 136 178 65 137 1 1 138 3 2 139 132 249140 479 >513 141 182 102 142 10 7 143 102 30 144 59 28 145 ~32 9 146 8338 147 10 6 148 68 30 149 251 138 150 138 91 151 490 66 152 62 87 153316 316 155 437 339 156 42 51 157 >513 417 158 23 20 159 >513 >513 16058 23 161 >513 >513 162 209 91 163 >513 >513 164 145 71 165 45 11166 >513 >513 167 >513 ~427 168 214 112 169 200 102 170 >513 >513 171155 102 172 >513 >513 173 78 52 174 >513 >513 175 9 11 176 16 15 177 6042 178 >513 >513 180 3 1 181 ~447 ~398 182 1 0 183 6 3 184 2 2 185 ~331148 186 339 182 187 >513 >513 188 22 15 189 >513 >513 192 >513 >513193 >513 >513 194 >513 >513 195 ~102 47 196 182 91 197 65 43 198 >513200 199 >513 309 200 n.d. n.d. 201 42 26 202 >513 >513 203 98 44204 >513 >513 205 >513 >513 206 >513 >513 207 372 105 208 186 83209 >513 >513 210 245 151 211 36 22 212 398 328 213 33 25 214 >513 >513217 79 49 218 >513 >513 219 >513 >513 220 >513 >513 222 >513 >513223 >513 >513 224 468 >513 225 102 87 226 20 13 227 27 20 228 >513 347229 186 96 230 145 141 231 ~457 398 232 >513 >513 234 n.d. n.d. 235 21479 236 >513 >513 237 20 11 238 219 157 239 >513 >513 240 >513 >513241 >513 >513 242 >513 >513 243 >513 >513 244 >513 >513 245 >513 >513249 71 52 250 5 6 251 52 23 252 >513 >513 262 n.d. n.d. 264 >513 355 272151 ~85 273 447 ~257 276 85 46 278 295 178 279 145 115 280 ~275 158 28115 15 282 7 6 286 398 245 287 151 48 291 n.d. n.d. 292 437 234 293 n.d.n.d. 295 >513 >513 296 42 14 297 20 300 71 85 301 >513 427 302 76 76 30387 79 304 >513 295 308 >513 >513 309 n.d. n.d. 316 >513 >513317 >513 >513 318 >513 ~295 328 9 9 332 ~316 112 333 >513 148 336 85 46337 204 71 338 275 98 339 >513 >513 340 76 50 341 46 26 342 n.d. n.d.343 389 178 347 219 63 350 n.d. n.d. 351 n.d. n.d. 352 14 21 353 52 18354 >513 >513 355 >513 437 358 >513 >513 359 >513 >513 360 >513 >513 361229 263 362 229 263 364 49 43 365 20 13 366 102 91 368 120 ~23373 >513 >513 375 n.d. n.d. 376 105 85 381 209 117 382 513 91 383 23 6384 20 7 385 32 20 386 >513 >513 389 39 28 390 n.d. n.d. 391 >513 >513394 ~26.3 18 395 >513 >513 396 >513 >513 397 >513 >513 398 >513 >513399 >513 >513 400 457 ~371.54 401 >513 >513 402 >513 >513 117a n.d. n.d.118a n.d. n.d. 122a 12 9 123a >513 380 154a 30 23 154b >513 >513 184a 32 184b 3 2 184c 4 2 237a 6 4 237b >513 >513 237c 26 11 237d >513 >513243a >513 >513 243b >513 >513 246a 44 24 246b n.d. n.d. 257b >513 >513257c >513 >513 262a n.d. n.d. 262b n.d. n.d. 279a 58 41 279b 59 >513280a 87 45 280b >513 >513 281a 5 3 281b >513 >513 283a 81 52 283b n.d.n.d. 284a 90 61 284b >513 >513 286a >513 >513 286b n.d. 204 287a 31 34287b >513 417 292a 155 98 292b >513 >513 295a >513 >513 295b >513 >513296a 23 16 296b 468 339 297a 200 204 297b 7 3 298a 135 47 298b 501 >513299a ~45 56 299b >513 >513 300a 29 19 300b n.d. n.d. 302a >513 >513 302b54 39 309a 9 8 309b 363 282 312a >513 >513 312b >513 >513 313a 257 166313b >513 >513 314a ~407 >513 314b 191 n.d. 315a 195 >20.42 315b ~110~85 319a >513 >513 319b >513 >513 320a 20 17 320b n.d. n.d. 321a 18 8321b n.d. n.d. 322a >513 >513 322b 42 26 323a n.d. n.d. 323b 209 100324a 13 10 324b n.d. n.d. 325a n.d. n.d. 325b >513 263 329a 14 6329b >513 >513 334a 339 219 334b >513 >513 335a 5 2 335b 188 207 338a115 68 338b >513 >513 339a >513 407 339b >513 >513 344a >102 56344b >513 ~513 345a 79 28 345b >513 >513 346a 178 68 346b >513 >513347a >513 >513 347b 85 60 348a 288 138 348b >513 >513 349a 4 2 349b 479302 356a n.d. n.d. 356b n.d. n.d. 357a >513 >513 357b 30 14 363a ~126 74363b n.d. n.d. 364a 35 26 364b >513 >513 365a 52 35 365b n.d. n.d.367a >513 >513 367b >513 >513 369a ~363 251 369b >513 >513 370a 107 40370b >513 >513 371a 10 2 371b >513 251 374a 32 17 374b >513 >513 379a~29 22 379b n.d. n.d. 380a n.d. n.d. 380b >513 >513 388a n.d. n.d. 388b38 19 391a n.d. n.d. 391b n.d. n.d. 392a n.d. n.d. 392b n.d. n.d.393a >513 >513 393b >513 >513 395a >513 >513 395b >513 >513397a >513 >513 397b ~513 >513 403a ~275 ~132 403b >513 >513404a >513 >513 404b 398 295 405a >513 >513 405b 44 33 406a 8 4406b >513 >513 407a n.d. n.d. 407b n.d. n.d. 408a n.d. n.d. 408b n.d.n.d. 83a >513 >513 83b >513 >513 83c >513 >513

Prophetic Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of Formula (I), including any tautomer or stereoisomeric formthereof, or a N-oxide, a pharmaceutically acceptable addition salt or asolvate thereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1, Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution or in 10% by volume propyleneglycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

The invention claimed is:
 1. A method for inhibitingphosphoinositide-3-kinase activity in a human in need thereof,comprising administering to the human a therapeutically effective amountof a compound of the following formula:

or a pharmaceutically acceptable addition salt thereof.
 2. The method ofclaim 1, wherein the human suffers from a disease or condition selectedfrom the group consisting of allergy, asthma, an autoimmune disorder, acancer, a cardiovascular disease, graft rejection, an inflammatorydisease, a kidney disease, a lung injury, multiorgan failure, aneurodegenerative disease, pancreatitis, platelet aggregation, spermmotility, and transplantation rejection.
 3. The method of claim 2,wherein the disease or condition is a cancer.
 4. The method of claim 3,wherein the cancer is prostate cancer.